Dagher, Therapeutic Potential of Quercetin To Alleviate Endothelial Dysfunction in Age-Related Cardiovascular Diseases O

REVIEW
published: 30 March 2021

doi: 10.3389/fcvm.2021.658400
Therapeutic Potential of Quercetin to

Alleviate Endothelial Dysfunction in
Age-Related Cardiovascular
Diseases
Olina Dagher 1,2,3*, Pauline Mury 3 , Nathalie Thorin-Trescases 3 , Pierre Emmanuel Noly 2,3 ,
Eric Thorin 2,3 and Michel Carrier 2,3
1
Department of Cardiac Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada, 2 Department
of Surgery, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada, 3 Center for Research, Montreal Heart
Institute, Montreal, QC, Canada
The vascular endothelium occupies a catalog of functions that contribute to the

Edited by: homeostasis of the cardiovascular system. It is a physically active barrier between
Lamiaa A. Ahmed,
circulating blood and tissue, a regulator of the vascular tone, a biochemical processor
Cairo University, Egypt
and a modulator of coagulation, inflammation, and immunity. Given these essential roles,
Reviewed by:
Suowen Xu, it comes to no surprise that endothelial dysfunction is prodromal to chronic age-related
University of Science and Technology diseases of the heart and arteries, globally termed cardiovascular diseases (CVD). An
of China, China
Owen Llewellyn Woodman, example would be ischemic heart disease (IHD), which is the main cause of death from
Monash University, Australia CVD. We have made phenomenal advances in treating CVD, but the aging endothelium,
*Correspondence: as it senesces, always seems to out-run the benefits of medical and surgical therapies.
Olina Dagher
Remarkably, many epidemiological studies have detected a correlation between a
olina.dagher@ahs.ca
flavonoid-rich diet and a lower incidence of mortality from CVD. Quercetin, a member
Specialty section: of the flavonoid class, is a natural compound ubiquitously found in various food sources
This article was submitted to
such as fruits, vegetables, seeds, nuts, and wine. It has been reported to have a wide
Cardiovascular Therapeutics,
a section of the journal range of health promoting effects and has gained significant attention over the years. A
Frontiers in Cardiovascular Medicine growing body of evidence suggests quercetin could lower the risk of IHD by mitigating
Received: 25 January 2021 endothelial dysfunction and its risk factors, such as hypertension, atherosclerosis,
Accepted: 05 March 2021
Published: 30 March 2021
accumulation of senescent endothelial cells, and endothelial-mesenchymal transition
Citation:
(EndoMT). In this review, we will explore these pathophysiological cascades and their
Dagher O, Mury P, interrelation with endothelial dysfunction. We will then present the scientific evidence to
Thorin-Trescases N, Noly PE, Thorin E quercetin’s anti-atherosclerotic, anti-hypertensive, senolytic, and anti-EndoMT effects.
and Carrier M (2021) Therapeutic
Potential of Quercetin to Alleviate Finally, we will discuss the prospect for its clinical use in alleviating myocardial ischemic
Endothelial Dysfunction in injuries in IHD.
Age-Related Cardiovascular Diseases.
Front. Cardiovasc. Med. 8:658400. Keywords: endothelial (dys)function, flavonoids, quercetin, hypertension, atherosclerosis, senescence, aging,
doi: 10.3389/fcvm.2021.658400 ischemia-reperfusion
Frontiers in Cardiovascular Medicine | www.frontiersin.org 1 March 2021 | Volume 8 | Article 658400

Dagher et al. Alleviating Endothelial Dysfunction With Quercetin
INTRODUCTION additional, yet poorly explored, therapeutic avenue. Finally, we

will discuss its potential use in secondary and tertiary prevention
It is impressive to think that one single layer of cells of endothelial dysfunction by taking the example of myocardial
tightly regulates homeostasis of the cardiovascular system. ischemic injury in IHD.
With its enormous surface area and its key location at the
interface between circulating blood and tissue, the vascular
endothelium has multiple physiological functions, such as ENDOTHELIAL DYSFUNCTION AS A
modulation of the vascular tone and local regulation of TARGET FOR PREVENTING
coagulative, immune and inflammatory stimuli, in addition to CARDIOVASCULAR DISEASES
providing a semipermeable barrier (1). A normally functioning
endothelium appropriately arbitrates between opposing states Conceptually, the core feature of endothelial dysfunction is a
of vasodilatation and constriction, permeability and non- disrupted nitric oxide (NO) bioavailability as a consequence
permeability, adhesion and non-adhesion, as well as anti- of a reduced production by endothelial NO synthase (eNOS)
thrombotic and pro-thrombotic conditions (1). Therefore, it is from L-arginine and in favor of free-radicals generation
intuitive to imagine that a distortion in this equilibrium can (11). Different causal paths have been implicated, including
result in adverse effects (2). Indeed, many cardiovascular diseases shear stress, dyslipidemia, hyperglycemia, insulin resistance,
(CVD) are either a direct or indirect result of a dysfunction hyperhomocysteinemia and, more recently, senescence and
of the endothelium that fails to maintain moment-to-moment EndoMT. The mechanisms by which they can lead to endothelial
homeostasis, ultimately creating maladaptation in meeting organ dysfunction and CVD pathogenesis are broad and complex. Most
metabolic demand and chronic damages (3). An example would often, many of these factors accumulate in one person where they
be ischemic heart disease (IHD), which is the main cause of cross talk and synergistically enhance dysfunction of the arterial
death from CVD (1). IHD itself represents an umbrella term wall. Treatment of these cardiovascular risk factors was shown
for a group of clinical syndromes characterized by myocardial to reverse endothelial dysfunction and simultaneously improve
ischemia such as stable angina and acute coronary syndromes. the incidence of cardiac events (12). Here, we will focus our
Risk factors for endothelial dysfunction, and, by extension, attention on the mechanistic connections between hypertension,
IHD, include smoking, obesity, insulin resistance, diabetes, atherosclerosis, senescence, and endothelial dysfunction.
hypercholesterolemia, and physical inactivity (4). Phenomenal
advances in pharmacology have enabled us to therapeutically Endothelial Dysfunction in Hypertension
target many of these risk factors, resulting in a significant and Atherosclerosis
decline in cardiovascular mortality over the last four decades (5). Endothelial dysfunction is seen as an early step in the
However, the use of drugs remains hampered by their toxicity, development of hypertension and atherosclerosis (13, 14).
patients’ tolerance and the limits of their clinical efficacy. In Indeed, the functional characteristics of endothelial dysfunction
addition, endothelial dysfunction inevitably occurs with normal include an impairment of endothelium-dependent vasodilation
aging, fuelled by a process of irreversible cell cycle arrest termed and endothelial activation marked by pro-inflammatory,
senescence (6). For these reasons, there has been a burgeoning proliferative, and procoagulatory states (14).
interest in introducing complementary therapies, such as dietary Upon activation, endothelial cells switch from a predominant
components, in the prevention of CVD (7). NO signaling to an oxidative stress signaling mediated by reactive
Among promising nutraceuticals, a group of naturally oxygen species (ROS) (15). While NO promotes inhibition
occurring compounds found in plants, called flavonoids, have of pro-inflammatory cytokine secretion, thrombosis, smooth
become increasingly popular. As early as in the 1990s, data from muscle cell proliferation and immune cell extravasation, ROS
epidemiological studies have established a connection between induce nuclear transcription factor kappa B (NFκB) signaling, the
a higher intake of flavonoid rich diets and a lower incidence main regulator of inflammation (15). In addition, the diseased
of CVD (8). Quercetin has been singled out among flavonoids endothelium acquires a pro-inflammatory state and becomes
mainly because of its ubiquitous presence in our diets. It was also more permeable, allowing the avid accumulation of oxidized
the first flavonoid to be discovered, precisely in the context of a low-density lipoproteins (ox-LDLs) and macrophages in the
vascular pathology. Indeed, in 1936, Albert Szent-Gyorgyi and his subintimal layer, culminating in foam cell formation and fatty
collaborators published the case of a patient who recovered from streaks which are hallmarks of atherosclerosis development (15).
a bleeding disorder after receiving an infusion of a substance On the other hand, a defective L-arginine/NO pathway, impaired
extracted from a Hungarian red pepper, which they called responsiveness to exogenous NO and reduced generation of
vitamin P, for “permeability” (9). Quercetin has since gained platelet NO result in a state of predominant vasoconstriction and
significant attention for its wide range of biological activities, higher resting blood pressure (14). Furthermore, atherosclerotic
some of which can mediate cardioprotective effects (10). In this lesions develop preferentially at arterial bifurcations, branching
review, we will examine quercetin’s potential to alleviate CVD points and vessel curvatures, where the blood flow is disturbed
by protecting endothelial function. We will focus on three core (16). This suggests the importance of hemodynamic forces and
pathophysiological mechanisms: atherosclerosis, hypertension mechanical stress, hence of hypertension, in the initiation of
and endothelial senescence. We will also cover quercetin’s effects atherosclerosis. When considering the role of atherosclerosis in
against endothelial-mesenchymal transition (EndoMT), as an hypertension, a number of studies reported that atherosclerotic

segments were accompanied by an altered function of eNOS (TGF-β)] and hundreds of signaling molecules such as damage-
in which it produces superoxide instead of NO (17). NADPH associated molecular patterns, proteases, extracellular matrix
oxidase (NOX), which is induced by ox-LDLs, was shown to lie (ECM) components [matrix metalloproteinases (MMPs)],
upstream to this eNOS alteration (17). Referred to as “eNOS serine/cysteine proteinase inhibitors (SERPINs), tissue inhibitor
uncoupling,” this oxidative pathway is also present in aged of metalloproteinases and cathepsins), proteases, bradykinins,
microvessels (18). It goes without saying that oxidative stress and hemostatic factors (27–29). Without a doubt, the SASP
plays a critical role in endothelial dysfunction, and, as we will plays an essential role in normal tissue development (30), wound
next, in stress-induced senescence. healing (31), and cardiac repair (32). Transient expression of
This interconnection between endothelial dysfunction, SASP during the acute phase of a tissue injury assists with
atherosclerosis and hypertension has been confirmed clinically: repair and remodeling by recruiting the immune system to clear
using arterial dilatation as a non-invasive measure for damaged cells and by stimulating progenitor cells to repopulate
assessing endothelial function, endothelial dysfunction has the damaged tissue (33). However, senescence becomes a double-
been documented in both hypertensive and atherosclerotic edged phenomenon when ineffective clearance of SCs prolongs
patients (12, 19–22). Using acetylcholine to induce endothelium- their residency. In the concept of “inflamm-aging,” aberrant focal
dependent dilation, a reduction in arterial dilation was observed accumulation of SCs creates a pro-inflammatory environment
in the forearm and coronary beds of patients with essential favorable for the onset of various pathological conditions,
hypertension (12). Furthermore, the response to acetylcholine including endothelial dysfunction (34). Indeed, a growing body
and adenosine was significantly decreased in patients with of evidence shows that SCs are prominent in diseased vascular
hypertension and left ventricular hypertrophy, indicating an walls (35), including in intact arteries from IHD patients (36, 37).
impairment in both endothelium-dependent and endothelium- Furthermore, although vascular cells have a finite replicative
independent vasodilation (19). Ludmer et al. provided the first capacity, a combination of both damage-dependent replicative
evidence of compromised endothelium-dependent vasodilation senescence and stress-induced senescence might be especially
in the presence of atherosclerosis in humans (20). Using the relevant to premature vascular aging and endothelial dysfunction
acetylcholine test, they reported a paradoxical constriction in (3, 38).
the coronary arteries of patients with both mild and advanced
coronary artery disease (20). Endothelial dysfunction was
also present in the vasculature of patients with coronary The Vicious Circle of Endothelial
risk factors but no angiographic or ultrasound evidence of Dysfunction
structural coronary artery disease (21). These studies suggest Senescence of a vascular wall leads to two immediate
that endothelial dysfunction is detectable from the early consequences: induction of a pro-inflammatory environment
stages of atherosclerosis and that it might even be a trigger by the SASP and a reduction in the turnover of vascular cells
mechanism (22). (Figure 1). In atherogenesis, plaque initiation could be driven
Now endothelial dysfunction can be extended beyond the by senescent endothelial cells through their increased secretion
concept of a damaged conduit vessel to that of a defective vascular of chemoattractant factors and adhesion molecules, which allow
wall composed of layers of cells that are prone to aging. If for the initial invasion of circulating monocytes into the vessel
endothelial dysfunction is the primum movens of hypertension wall (39). Conversely, clearance of senescent vascular cells
and atherosclerosis, an upstream connection between the three lowered the pathogenesis of atherosclerosis in a mouse model of
could be linked to senescence. severe dyslipidemia (36). In addition, a senescent endothelium
presents an altered cellular lining, causing a break in selective
permeability (40). This can facilitate migration of ox-LDLs to
Senescence: The Natural Fate of Aging the subendothelial layers. The SASP can also stimulate vascular
Cells smooth muscle cells to secrete elastase and MMPs, which can
Successive replication (23) and harmful stimuli such as DNA digest components of the extracellular matrix (41). An amplified
damage, oxidative stress, and induction of mitochondrial degradation of the extracellular matrix could create a rupture-
dysfunction eventually impose a state of permanent proliferative prone vulnerable plaque. Thus, senescence of vascular cells leads
arrest on cells (24, 25). This phenomenon, termed “senescence,” to vascular inflammation and plaque progression. This vascular
is well-recognized as one of the nine hallmarks of aging (26). inflammation also raises the possibility of a multistep role of
Despite being in cell cycle arrest, senescent cells (SCs) undergo senescence in hypertension, although the link between the two
profound phenotypic changes and remain metabolically active. is less clearly established. The SASP could play a role in the
In response to stress, they secrete a set of proteins collectively dysregulation of the vascular tone: as an example, it was found to
termed the senescence-associated secretory phenotype activate the renin–angiotensin–aldosterone system (35).
(SASP) (27, 28). These include pro-inflammatory cytokines With aging, the clearance of SCs by the immune system
(interleukin (IL)-6, IL-8, membrane cofactor proteins (MCPs) is decreased, contributing to the accumulation of SCs
and macrophage inflammatory proteins) and chemokines, (33, 42). Senescence therefore begets senescence (Figure 1),
immune modulators, growth factors [hepatocyte growth a phenomenon that has been validated in mice (43). As
factor, fibroblast growth factors, granulocyte-macrophage senescence induces more senescence, the processes involved
colony-stimulating factor, or transforming growth factor beta in the pathogenesis of atherosclerosis and hypertension are

FIGURE 1 | Schematic representation of the proposed connections between senescence, hypertension, atherosclerosis, and endothelial dysfunction. Normal aging
and deleterious stimuli induce senescence in endothelial cells (ECs), vascular smooth muscle cells (VSMCs), and foam cells. Accumulation of these senescent cells
favors a pro-inflammatory state of the vascular bed through the senescence-associated secretory pathway (SASP). In turn, the SASP promotes pathological changes
leading to the development of hypertension and atherosclerosis. In a feedback manner, hypertension and atherosclerosis induce more stressors to an already
dysfunctional and senescent vessel wall. This vicious circle translates into endothelial dysfunction and, eventually, ischemic heart disease. Other causal pathways of
endothelial dysfunction include hyperglycemia, insulin resistance, abnormal endothelial-to-mesenchymal transition (EndoMT), genetic predisposition and detrimental
lifestyle habits such as smoking. ET-1, endothelin-1; MMP, matrix metalloproteases; NO, nitric-oxide; RAAS, renin–angiotensin–aldosterone system; ROS, reactive
oxygen species.
further amplified. In parallel, important changes in the extra- atherosclerosis through shear stress (3). As mentioned before,
cellular matrix (ECM) protein composition occur with aging other cardiovascular risk factors often coexist, such as metabolic
and promote arterial stiffening (44). A rigid arterial wall disturbances, obesity, smoking or genetic predisposition,
causes systolic hypertension, which in turn, contributes to accelerating this deleterious process (12). The vascular

wall eventually gets caught into a vicious circle where it Bioavailability and Pharmacology
must face more stressors with less protective capacities (3). The chemical structure of aglycone quercetin makes it
Therefore, it is possible to acknowledge a cyclical, rather than hydrophobic (52). Its solubility in water is 2.1 mg/L at
sequential, relationship between senescence, hypertension and 25◦ C, while it is up to 2 g/L in ethanol (52). This physical
atherosclerosis, all contributing to endothelial dysfunction. In property limits its absorption and practical use in preparation
the next sections, we will explore quercetin’s potential to target forms as a dietary supplement. Initial investigations on
this triad of endothelial dysfunction. the pharmacokinetics of quercetin in humans suggested
very poor oral bioavailability after a single oral dose
(∼2%) (53). The absorption was found to increase to 3–
QUERCETIN
17% when quercetin was consumed in a glycosidic bond
Classification and Structure compared to its aglycone form (53). Different delivery
Quercetin is part of a larger family of molecular compounds, systems using nanotechnology have since been developed
named flavonoids, which share a common hydroxylated 3- to further improve its water solubility and bioavailability, for
ringed skeleton with attached hydroxyl groups (45) (Figure 2). example, by binding it to solid lipid carriers or nanosized
Combined with the pyrocatechol, a benzene ring, this chemical polymeric micelles (54). A pharmacokinetic study in beagle
structure allows them to act as radical scavengers, explaining, dogs showed that quercetin encapsulated in polymeric
in part, flavonoids’ antioxidant property (45). Flavonoids are micelles induces a 2.19-fold longer half-life and a relative
themselves part of a large class of plant-derived substances oral bioavailability increased by 286% as compared to free
named polyphenols (46). Flavonoids include several subclasses quercetin (55).
such as flavonols, flavones, flavanols, flavanones, isoflavones, and Since dietary quercetin is usually present in its glycosylated
anthocyanins (46). They exist in most of the plants and play form, it can be rapidly hydrolyzed by β-glucosidases in the
a variety of biological activities involved in vegetative growth digestive tract, which makes it easier for absorption by the colonic
(46). Being phytochemicals, flavonoids cannot be synthesized by mucosa (56). It is then transferred to the liver through the
humans or animals, but they are ubiquitously present in our diet portal circulation where it undergoes first-pass metabolism and is
(46). They are found in virtually all fruits and vegetables, as well almost completely metabolized by glucuronidation, methylation,
as in seeds, nuts, tea and red wine (46). The mean daily intake of or sulfonylation (56, 57). Peak plasma concentration following
flavonoids in Australian, European and US adult populations has an oral quercetin dose is reached anywhere from 0.6 to
been estimated at 435 mg/day (47). 4 h (58–60). Quercetin glucuronides are the main circulating
Structurally, quercetin is not only found in its free (aglycone) metabolites and are rapidly eliminated in the urines (57, 60).
form, but also in various conjugated forms with glycosides or This short elimination half-life is another limit to quercetin’s
methyl ethers attached to the hydroxyl groups. Glycosylation medical use. Furthermore, quercetin’s metabolism seems to
preferentially occurs at the 3-hydroxyl position, such as quercetin be dependent on individual characteristics. A correlation
3-O-β-D-glucoside (isoquercetrin) or quercetin 3-O-galactoside between β-glucuronidase activity and the apolipoprotein (apo)
(hyperoside), whereas methylation usually occurs at the 3’, 4’, or E phenotype may explain the efficacy of quercetin in patients
7-hydroxyl positions, such as 3-methylquercetin (isorhamnetin) with apoE3 phenotype as opposed to those expressing apoE4
(48). Some quercetin derivatives even contain both glycosyl (61, 62). On the other hand, an increased expression of
and ethyl groups. For example, tamarixetin has a glucose β-glucuronidase was correlated with inflammation, raising
residue at the 3’ position and a methyl group at the 4’ the hypothesis that quercetin may be more effective under
position (48). Extensive studies of the biological activities inflammatory conditions (63). This is especially favorable
of quercetin have shown that the various derivatives have as endothelial dysfunction is often associated with a pro-
different levels of efficacy. For example, free quercetin was inflammatory state.
found to have the strongest antioxidant activity, confirming When it comes to pharmacokinetic interactions, conclusions
the important contribution of unbound hydroxyl groups (49). are still open to debate. Some studies investigated the effects
Among its metabolites, free quercetin was also the most effective of quercetin on the cytochrome P450 system and have noted a
recombinant human angiotensin-converting enzyme (ACE) 2 potential inhibitory effect of quercetin on the activity of selected
inhibitor (50). Tamarixetin and isorhamnetin demonstrated enzymes (64). Studies in pigs have shown that quercetin can
a stronger inhibition of lipid peroxidation compared to decrease bioavailability of cyclosporine and increase that of
quercetin (49, 51). Tamarixetin also exhibited the highest anti- digoxin, verapamil and various chemotherapeutic agents (65–
inflammatory activity, suggesting that unlike the antioxidant 67). However, conflicting results between in vitro and in vivo
activity, anti-inflammatory activity is not correlated with studies have been found (67). Quercetin was also reported to bind
the number of free hydroxyl groups (49). These disparities to DNA gyrase enzyme in bacteria, which could competitively
in biological activities prompt the synthesis of particular inhibit fluoroquinolone antibiotics’ activity (68). One case
metabolites that present the highest efficacy of a desired effect. report of a clinically relevant warfarin interaction resulting in
This can be achieved by inducing glycosylation or methylation supratherapeutic international normalized ratio values has been
using purified biocatalysts in vitro and native or metabolically documented in an elderly patient who ate large quantities of
engineered microorganisms (48). scuppernongs, a quercetin-containing muscadine grape (69).

FIGURE 2 | Classification and chemical structure of quercetin, a family member of flavonoids. Quercetin is a pentahydroxyflavone, having five hydroxyl groups placed
at the 3-, 3’-, 4’-, 5-, and 7-positions. Combined with the pyrocatechol, a benzene ring, this chemical structure allows them to act as radical scavengers, explaining, in
part, quercetin’s strong antioxidant properties.
Safety Profile Nephrotoxicity has been reported with high intravenous doses in
In the 1970s, in vitro mutagenicity of quercetin in the Ames cancer patients (67). Quercetin was not found to cause critical
test was reported, leading to concerns about its safety (70). adverse effects on fetal growth in rats, but human studies are
Later, in vivo studies contradicted these findings and showed not available (67). Therefore, dosages above those found in foods
that quercetin may be protective against carcinogens (70). Since should be avoided by pregnant women and nursing mothers (67).
1999, it is classified as a group 3 agent (“not classifiable as to
its carcinogenicity” to humans) by the International Agency for
Research on Cancer (70). In 2010, QU995, a highly pure form of A Recent Resurgence in Interest
quercetin, was granted a “generally recognized as safe” (GRAS) While it was previously known as “vitamin P,” the National
status by the U.S. Food and Drug Administration (59). Many Nutrition Institute withdrew its status in 1950 when it was found
other quercetin formulas have since been developed and made to be a non-essential nutrient (71). Added to a mislabeling of
widely available over the counter as oral dietary supplements or genotoxicity, altogether this contributed to a loss of interest
added ingredient to numerous multivitamin preparations. in the molecule. In 1993, however, the Zutphen Elderly Study
Quercetin is generally well-tolerated. Some minor side-effects first reported a 50% reduction of mortality from IHD in Dutch
such as mild headache, nausea, and tingling of the extremities men who consumed >29 mg flavonoids/day compared with
were observed in long-term supplementation at 1,000 mg/day those who consumed <19 mg (72). Around the same time, the
(67). In Canada, the recommended maximum daily dose is concept of the French paradox emerged from the contradictory
1,200 mg (67). A therapy as long as 12 weeks showed no observation of a low IHD-related mortality despite high intakes
evidence of toxicity, but data on long-term safety are lacking (67). of dietary saturated fat among the French population (73).

FIGURE 3 | Timeline of the cumulative number of published results, from 1980 to 2020, of an online PubMed literature search using “Quercetin” (dotted line) and
“Quercetin [and] Cardiovascular” (solid line) as the search term. Note the progressive increase from the mid-1990s, coinciding with publication of observational studies
associating flavonoid consumption with lower cardiovascular risks. Search performed January 10, 2021 (www.ncbi.nlm.nih.gov/pubmed).
Most debates have focused on high consumption of red wine, topic of interest (158). Considerable evidence from experimental
which contains a variety of polyphenols, including flavonoids data indicates that quercetin may protect against atherosclerosis
(73). Other epidemiological studies soon followed and showed by interfering with multiple pathways involved in disease
a positive correlation between dietary intake of flavonoids and a progression (Table 1). Several high-fat animal models exhibited
reduced incidence of stroke, myocardial infarction and mortality reduced atherosclerotic plaque areas when exposed to quercetin
from IHD (74). (76–84). This observation was associated with a prevention
Over the years, quercetin was found to have a diverse array of of atherosclerosis-related acute aortic syndromes: in a mouse
biological properties, such as anti-inflammatory, anti-oxidative, model with an exaggerated degeneration of the elastic lamina:
anti-platelet, anti-diabetic, anti-histaminic, anti-carcinogenic, administration of quercetin 2 weeks before inducing aortic
anti-bacterial, immunomodulating, and neuroprotective (75). diseases was found to reduce the incidence of aneurysms,
These prominent effects have sparked attention and hope among dissections and aortic ruptures (109).
the scientific community. As of the end of 2020, there are more First, quercetin could positively regulate the metabolism of
than 20,000 published articles on quercetin, and this number lipids. A recent systematic and meta-analysis of 16 randomized
exceeds 120,000 when including all flavonoids (Figure 3). Despite controlled trials (RCTs) published between 2007 and 2017 looked
quercetin being discovered for its role in treating capillary wall at the effects of quercetin on lipid profiles of patients with
dysfunction, it has gained more popularity in oncology and sports metabolic syndrome traits (112). A pooled analysis revealed
medicine, each counting 50% more publications than the field of that quercetin leads to a significant reduction in total and
cardiovascular research. However, its promising benefits for the LDL cholesterol, without affecting triglyceride levels (112). The
endothelium cannot be ignored (Table 1). daily doses and treatment durations used in the trials varied
greatly, from 3.12 to 3,000 mg/ day and from 3 to 12 weeks
(112). Another meta-analysis of 9 RCTs done in overweight and
CARDIOVASCULAR PROTECTIVE obese subjects found that quercetin supplementation significantly
PROPERTIES OF QUERCETIN reduces LDL cholesterol levels at doses of ≥250 mg/day and
Anti-Atherosclerotic Effects of Quercetin for a total dose ≥14,000 mg (159). Similar findings were
With the increasing epidemic of the metabolic syndrome, observed in metabolically healthy non-obese adults after an
the burden of atherosclerosis-related disorders persists despite 8-week regimen, with comparable effects among men and
the current pharmacologic treatment of dyslipidemia (64). women (113). Recent studies have highlighted the influence
Therefore, finding additional anti-atherogenic drugs remains a of the gut microbiota on host metabolic health through its

TABLE 1 | Summary of the main in vitro and in vivo cardiovascular effects of quercetin.
Effects Subjects Evidence and possible mechanisms References
Anti- Animals Reduced atherosclerotic plaque areas (76–84)

atherosclerotic
Increased concentration of SCFAs in the intestinal tract of ApoE−/− mice (85)
Promoted cholesterol-to-bile acid conversion and cholesterol efflux (78, 82, 86–92)
Downregulated PCSK9 expression in RAW264.7 cells and in ApoE−/− mice (90–92)
Normalized plasmatic/hepatic activities of HMG-CoA reductase in Wistar (93)
rats
Downregulated MMP-1, MMP-2, MMP-9 (94–98)
Decreased platelet aggregation in a concentration-dependent manner (99)
Inhibited thrombus formation through intracellular Ca2+ mobilization, (100)
granule secretion, and integrin activation
Inhibited phosphorylation of signaling proteins downstream of glycoprotein (100–102)
VI
Decreased ox-LDLs accumulation and foam cell formation (92, 95, 103–106)
Attenuated LDL oxidation (107, 108)
Decreased expression of adhesion molecules (ICAM-1, VCAM-1) (109–111)
Inhibited LOX-1 in RAW264.7 cells (95)
Decreased inflammatory cytokines, MCP-1 and COX-2 in RAW264.7 cells (95)
Humans Reduced total and LDL-cholesterol in patients with metabolic syndrome (112)
traits*
Reduced total and LDL-cholesterol in metabolically healthy patients* (113)
Decreased platelet aggregation in citrated whole blood in a (114)
concentration-dependent manner
Increased cAMP levels, inhibition of ADP-induced platelet aggregation (115, 116)
Decreased expression of adhesion molecules (ICAM-1, VCAM-1) (117, 118)
Reduced plasma concentration of ox-LDLs (119, 120)
Vasodilating Animals Improved Ach-induced relaxation of aortic rings harvested from (121)
hypertensive rats
Reduced systolic, diastolic, and mean arterial blood pressure in (122–124)
hypertensive rats
Improved endothelium-dependent aortic vasodilatation and eNOS activity (125–129)
Reduced eNOS uncoupling (124, 130, 131)
Inhibited LTCCs and enhanced VGKCs in coronary artery rings (132)
Reduced ACE activity in Wistar rats (133)
Humans Decreased expression of ET-1 gene/protein, and production of ET-1 (134–136)
Reduced systemic blood pressures in both normotensive and hypertensive (137–139)
patients*
Senolytic Animals Reduced viability of senescent HUVECs (140)
Combined with dasatinib, reduced the number of p16-positive SCs in fat (140)
and liver from old mice
Combined with dasatinib, increased median lifespan in old mice (43)
Increased the density of Sirt1 in aorta of ApoE–/– mice (141)
Decreased expression of β-galactosidase and improved cell morphology of (141)
HAECs
Humans Decreased expression of AATK, CDKN2A, and IGFBP3 in HAECs (141)
Combined with dasatinib, reduced the number of adipose tissue SCs and (43, 142)
circulating SASP factors
Myocardial Animals Alleviated ischemia-induced reduction in LVSP (143–147)
protectant
Reduced the decline in LVEF and FS induced by ischemia (148)
Reduced myocardial infarct size (149–151)
Lowered levels of CK, CK-MB, cTnT, and LDH post infarction (144, 147–149,
151–155)
Decreased leukocytes’ infiltration and edema in infarcted myocardium (149, 152, 153)
(Continued)

TABLE 1 | Continued
Effects Subjects Evidence and possible mechanisms References
Inhibited HMGB1 and TLR4 in cardiomyocytes (151, 153)

Up-regulated PPAR-γ positive myocardial cells (148)
Protected against calcium overload by downregulating calpain 1 and 2 (152)
Humans Reduced levels of IL-1β and TNF-α in patients with stable angina (156)
Improved profile of cardiac biomarkers and LVEF in patients with acute (157)
myocardial infarction
* From a meta-analysis of randomized controlled trials. AATK, apoptosis-associated tyrosine kinase; ACE, angiotensin-converting enzyme; ADP, adenosine diphosphate; CDKN2A, p16,
cyclin-dependent kinase inhibitor 2A; COX-2, cyclooxygenase-2; cAMP, cyclic adenosine monophosphate; CK, creatine kinase; CK-MB, creatine kinase-MB; cTnT, cardiac troponin T;
eNOS, endothelial nitric oxide synthase; ET-1, endothelin-1; FS, fractional shortening; HAECs, human Aortic Endothelial Cells; HMGB1, high mobility group box protein 1; HUVECs, human
umbilical vein endothelial cells; ICAM-1, intercellular adhesion molecule 1; IGFBP3, insulin-like growth factor binding protein-3; IL-1β, interleukin-1β; LDH, lactate dehydrogenase; LOX-1,
lectin-like ox-LDL receptor-1; LTCCs, L-type Ca2+ channels; LVEF, left ventricular ejection fraction; LVSP, left ventricular systolic pressure; MCP-1, monocyte chemoattractant protein-1;
MMPs, matrix metalloproteases; NO, nitric oxide; ox-LDLs, oxidized low density lipoproteins; PCSK9, proprotein convertase subtilisin/kexin type 9; PPAR-γ, peroxisome proliferator-
activated receptor gamma; SCs, senescent cells; SCFAs, short-chain fatty acids; SASP, senescence-associated secretory phenotype; SIRT1, sirtuin-1; TLR4, Toll-like receptor 4; TNF-α,
Tumor necrosis factor alpha; VCAM-1, vascular cell adhesion protein 1; VGKCs, voltage-gated K+ channel.
metabolites, especially short-chain fatty acids, which have been to 3.32, 2.99, and 1.11 µM upon co-administration of 2.5, 5, and
linked with improved lipid metabolism (160, 161). Quercetin 10 µM quercetin, respectively (100). In addition, isorhamnetin
was shown to increase the concentration of short-chain fatty and tamarixetin, two methylated metabolites of quercetin, were
acids in the intestinal tract of ApoE knockout (ApoE−/− ) shown to inhibit platelet aggregation and thrombus formation in
mice (85). Experiments on both in vivo rodent models and vitro through effects on activation processes such as intracellular
murine cultured macrophages (RAW264.7 cells) have suggested Ca2+ mobilization, granule secretion, and integrin activation
that quercetin promotes cholesterol-to-bile acid conversion and (100). Their antithrombotic effect was confirmed with laser-
cholesterol efflux by upregulating activity of hepatic CYP7A1, induced thrombi in mouse cremaster arterioles (100). In human
liver X receptor α, ABCG1, ABCA1, and LDLR (78, 82, 86–92). platelets, quercetin significantly increases cyclic AMP levels and
Quercetin also downregulated PCSK9 expression in RAW264.7 inhibits arachidonic acid and adenosine diphosphate (ADP)-
cells and in ApoE−/− mice (90–92). HMG-CoA reductase plays induced platelet aggregation (115, 116). Antiplatelet effects
a major role in the regulation of cholesterol metabolism as a of quercetin and its metabolites have also been associated
rate limiting enzyme in the pathway of cholesterol biosynthesis to inhibition of the phosphorylation of signaling proteins
(162). Results relating the effects of quercetin on HMG-CoA downstream of glycoprotein VI, namely the Src family tyrosine
reductase activity have been inconsistent (86, 93). Wistar rats kinases Fyn and Syk, the phospholipase Cγ2 and the linker for
fed with a diet containing 0.4% quercetin for 5 weeks did not activation of T cells (100–102).
express a change in the enzyme’s activity (86). However, in a Fourth, once oxidized in the intima, LDLs transform into
model of isoproterenol (ISO)-induced myocardial infarction in an antigenic factor, ox-LDLs, which attract monocyte-derived
Wistar rats, a 2 week oral quercetin pre-treatment at a dose of macrophages to the vascular wall, thereby initiating a phagocytic
10 mg/kg normalized plasmatic and hepatic activities of HMG- process leading to foam cell formation (163). Accumulation of
CoA reductase (93). Another protective mechanism of quercetin foam cells is an early step in the pathogenesis of atherosclerosis
involving enhancement of autophagy by aortic macrophages was (163). In their study, Kawai et al. used mAb14A2, a novel
highlighted in ApoE−/− mice (84). monoclonal antibody binding quercetin, to stain aortic samples
Second, quercetin has been suggested to downregulate in Japanese subjects (164). Their results revealed that quercetin
the expression of MMP-1, MMP-2, and MMP-9 in studies metabolites accumulate in atherosclerotic lesions, but not in
using molecular modeling techniques, cultured endothelial cells, normal-appearing aorta (164). In addition, intense staining
murine macrophage cells and in hypertensive rats, an effect that was primarily localized with foam cells, suggesting a potential
translates in the prevention of plaque instability (94–98). cellular target of quercetin (164). Several studies done on
Third, platelet aggregation at the site of an unstable plaque also cultured cells showed that quercetin can attenuate ox-LDLs
contributes to acute complications of atherosclerosis. Quercetin accumulation, foam cell formation, as well as ox-LDLs induced
was found to have an antiaggregatory effect on rat platelet-rich cytotoxicity and calcification (92, 95, 103–106). Interestingly,
plasma in a concentration-dependent manner (99). This was also quercetin significantly reduced plasma concentrations of ox-
observed in human citrated whole blood: using samples from 100 LDLs in two RCTs (119, 120). A retrospective comparison of
healthy volunteers, the minimal antiaggregatory concentration the participants’ apoE genotypes revealed no significant inter-
of quercetin was estimated at 15.26 µM (114). A synergistic group difference in the reduction of ox-LDLs between the
enhancement of antiplatelet effect was noted when quercetin apoE3 and apoE4 subgroups (62). This lowering effect on ox-
was added to aspirin (100). The half maximal inhibitory LDLs might be achieved through direct attenuation of LDL
concentrations (IC50 ) values for the inhibition of platelet oxidation: the lag time of LDL oxidation was increased by 3-
aggregation decreased from 10.83 µM when using aspirin alone, to 4-fold after administration of quercetin in vitro and in rats

(107, 108). The authors proposed two mechanisms contributing quercetin induced phosphorylation of eNOS at serine 1179 in a
to this attenuation of LDL oxidation: inhibition of copper- concentration, time-dependent manner; this effect was abolished
induced LDL oxidation, as well as up-regulation of Paraoxonase by H-89, an inhibitor of protein kinase A (128). Using the
1 (PON1) and its protective capacity against LDL oxidation same primary cell cultures, Khoo et al. proposed that quercetin
(107, 108). Lectin-like ox-LDL receptor-1 (LOX-1) is a scavenger stimulates eNOS phosphorylation at serine 1179 by causing a
receptor that mediates uptake of ox-LDLs by macrophages rapid increase in intracellular Ca2+ (129).
(165). Administration of anti-LOX-1 antibodies was shown to Other calcium-mediated vasoactive effects of quercetin have
inhibit atherosclerosis by decreasing these cellular events (165). been proposed. L-type Ca2+ channels (LTCCs) and voltage-gated
Quercetin was shown to block LOX-1 in RAW264.7 cells (95). K+ channels (VGKCs) play a tonic role in the regulation of
Moreover, ox-LDLs activate endothelial cells by inducing cell arterial vasomotricity and are commonly expressed in vascular
adhesion molecules, especially vascular cell adhesion molecule-1 smooth muscle cells (172, 173). LTCCs are involved in excitation-
(VCAM-1) and intracellular cell adhesion molecule-1 (ICAM-1) contraction coupling while VGKCs are critical for restoring the
(166). Quercetin was found to downregulate ICAM-1 expression resting membrane potential (172, 173). Large (big)-conductance
in diabetic rats and human endothelial cells (110, 117). Quercetin Ca2+ -sensitive potassium channels (BK) and VGKCs are closely
and isoquercetin were shown to attenuate VCAM-1 expression in associated with coronary arterial smooth muscle vasodilatation
mice, HUVECs and rat intestinal microvascular endothelial cells (174). Of note, aging is associated with a reduced expression
by suppressing multiple pathways including caveolin-1 (CAV- of BK channels in coronary arteries, which is consistent with a
1), Toll-like receptor 4 (TLR4) and NFκB (109, 111, 118). As higher frequency of spontaneous vasospasmic activity in elderly
previously mentioned, ox-LDLs also stimulate eNOS uncoupling people (174). Hou et al. showed that quercetin can inhibit LTCCs
and ROS overproduction by macrophages and endothelial cells and enhance VGKCs in rat coronary artery rings, resulting
via activation of NOX (167, 168). In ApoE−/− mice, quercetin in a decrease of the vasocontractions induced by high-K+
partially reversed NOX expression and inhibited ox-LDL induced depolarizing solution (132). Moreover, coronary vasodilation
ROS formation in macrophages (83). induced by quercetin was not lost after denuding the arterial rings
Finally, atherosclerosis is also a chronic inflammatory of their endothelium, suggesting that quercetin can also promote
disease mediated by a network of pro-inflammatory cytokines. its vasodilatory effect through VSMC-mediated mechanisms
Quercetin’s administration was associated with a decrease in (132). Cogolludo et al. noted that quercetin could activate BK
multiple inflammatory cytokines, such as IL-1α, IL-1β, IL- channels in coronary artery myocytes while generating hydrogen
2, IL-10, TNF-α, macrophage chemoattractant protein-1 and peroxide (H2 O2 ) (175). Although H2 O2 is considered as a
cyclooxygenase-2 (95). The impacts of quercetin on such a wide relaxing endothelium-derived hyperpolarizing factor (176) and
range of inflammatory markers are in favor of a multi-target effect can also activate the soluble guanylate cyclase as does NO (177,
of signal transduction. 178), the data of Cogolludo et al. may nonetheless represent an
instance where quercetin behaves as a pro-oxidant rather than
Vasodilating Effects of Quercetin a vasodilator.
Several ex-vivo reactivity studies have shown a vasodilating ability Endothelin (ET) is one of the most potent vasoconstrictors
of quercetin in rat aorta, portal vein, mesenteric arteries and and is mainly produced by the vascular endothelium (179). ET-
coronary arteries (169–171) (Table 1). In addition, Choi et al. 1 plays a major role in the homeostasis of the cardiovascular
reported that quercetin acutely improved acetylcholine-induced system. ET-1 has been associated with increased oxidative
relaxation of aortic rings harvested from two-kidney, one-clip stress and endothelial dysfunction in humans (179). It was
(2K1C) hypertensive rats (121). shown to stimulate eNOS uncoupling, therefore superoxide
Quercetin’s BP lowering effects were first documented in production, and promote vasoconstriction via activation of
vivo in spontaneously hypertensive rats (122). Rats exposed NOX (130, 180). ET-1 can further reduce NO bioavailability
to quercetin had a significant lower systolic (−18%), diastolic by interfering with eNOS expression through protein kinase C
(−23%), and mean (−21%) arterial BP (122). In normotensive (PKC)-mediated activation of STAT3 (181). These data indicate
rats, endothelial dysfunction induced by a high-fat high-sucrose that diminished ET-1 concentrations may be accompanied by
diet was prevented by the supplementation with quercetin for elevated NO bioavailability (181). Lodi et al. showed that
28 days: both endothelium-dependent aortic vasodilatation and quercetin significantly decreased expression of ET-1 in human
eNOS activity were improved by quercetin (125). The vasomotor umbilical artery smooth muscle cells and human vein endothelial
protective effects of quercetin were also demonstrated in mice cells (HUVECs) co-culture model exposed to TNF-α-induced
exposed to lipopolysaccharide-induced endotoxemia. Whether change in vasomodulatory molecules (134). Zhao et al. also
given before or after lipopolysaccharide injection, quercetin showed that quercetin decreases ET-1 production in thrombin-
dose-dependently restored eNOS expression while abolishing stimulated HUVECs in a concentration-dependent manner, with
inducible NO synthase (iNOS) (126). an IC50 of 1.54 µmol/L (135). In rat aortic rings, quercetin
Several hypotheses have been formulated regarding the prevented ET-1-induced PKC activation, with a subsequent
up regulation of eNOS activity induced by quercetin. Some decrease in superoxide production (130). Moreover, chronic
authors have suggested that quercetin phosphorylates eNOS by treatment with quercetin reduced blood pressure and improved
an AMP-activated protein kinase-dependent mechanism (127). endothelial function in deoxycorticosterone acetate (DOCA)-
Li et al. observed, in bovine aortic endothelial cells, that salt rats, a low renin model of hypertension in which ET-1

is overexpressed (123, 124). These effects of quercetin were these results indicate a significant anti-hypertensive effect of
associated with a reduction in both vascular and systemic quercetin supplementation only when doses ≥500 mg/day are
oxidative stress (124). Quercetin protective effects against taken for ≥8weeks (137). Another meta-analysis which included
eNOS uncoupling were even maintained under glucotoxic 896 participants across 17 RCTS mirrored the results obtained by
conditions (131). Serban et al., which indeed is the meta-analysis done by Huang
A RCT studied the acute effects of administering 200 mg of et al. (138). More recently, a meta-analysis of 8 RCTs conducted
quercetin in 12 healthy men (136). Blood and urine samples among patients with metabolic syndrome traits showed that
taken, respectively, 2 and 5 h after oral ingestion of quercetin quercetin supplementation significantly reduced systolic BP, yet
revealed a significant acute reduction in both the plasma did not affect diastolic BP (139). Clearly, trials directly comparing
and urinary concentrations of ET-1, translated into a reduced different doses and regimen durations are needed.
ET-1 production (136). This effect is substantial given the
relatively small dose used and the low bioavailability of quercetin. Senolytic Properties of Quercetin
Interestingly, it was reported that NO inhibits ET-1 production The accumulation of SCs in the aging and diseased vessel
through the suppression of NFκB (182). A second mechanism wall raises the possibility that reducing senescence might delay
involves the renin–angiotensin system: ACE inhibitors neutralize deterioration of vascular structure and function. In an elegant
ACE by binding a zinc atom at the active site of the enzyme, and seminal experiment, Baker et al. demonstrated that the
which slows conversion of angiotensin I to angiotensin II, a health span in progeroid mice can be enhanced by killing SCs
powerful vasoconstrictor (183), including in human coronary using a transgenic suicide gene (188). Elimination of SCs also
arteries (184). Quercetin can chelate metal ions, including zinc delayed progression of multiple age-related phenotypes, such
(185), and it is tempting to presume it can act as an ACE as cancer, cataract, sarcopenia, lordokyphosis, loss of adipose
inhibitor. However, available results have been discordant. In tissue and skeletal muscle fibers, as well as improved exercise
vitro, quercetin inhibited ACE activity in a concentration- capacity (188). Translating that same effect into a druggable
dependent manner, with an IC50 of 310 µM (186). This value compound sparked research interest and led to the recent concept
was significantly higher than that of captopril (0.02 µM) (186). of “senolytic therapy” (140). Formed by the words “senescence”
In Wistar rats receiving an angiotensin-1 infusion, Hackl et al. and “lytic” (destroying), a senolytic represents a molecule that
showed that an attenuation of the BP was obtained with both could specifically induce cell death in SCs (189). Based on the
oral and intravenous administration of quercetin (133). They knowledge that SCs survive despite their harsh internal state,
also reported a 31% reduction in ACE activity in the quercetin the hypothesis was that this would be achieved by targeting
group compared to the control group (133). In contrast, one their survival pathways and anti-apoptotic mechanisms (189).
double-blind placebo-controlled RCT did not find ACE activity An alternative strategy to interfere with senescence would be
inhibition after a single-dose of quercetin (187). In this study, five to reduce the burden of SASP. The advent of antibody-based
normotensive men and twelve hypertensive men ingested a total techniques such as sandwich enzyme-linked immunosorbent
of 1,095 mg quercetin and 10 h later, the mean BP was reduced assay, and large-scale molecular biology techniques such as
among the hypertensive patients by 5 mm Hg compared to the mRNA profiling, antibody arrays, proteomics or multiplex assays
placebo group (187). Plasma ACE activity, ET-1, and brachial have made the detection and measurement of several SASP
artery flow-mediated dilation were unaffected by quercetin, factors possible (190). These powerful tools therefore serve to test
suggesting that the reduction in BP in hypertensive men was pharmaceutical efficacy of drugs that target SASP (190). In the
independent of the changes in ACE and ET-1 activity, or NO following sections, we will see evidence suggesting that quercetin
bioavailability (187). eliminates SCs and reduces the SASP.
Serban et al. conducted a systematic review of 7 RCTs In 2008, quercetin was reported to increase longevity of
published between 1998 and 2014, looking at the effects of worms (191), but it was not until 2015 that its potential
quercetin on BP (137). Their meta-analysis revealed a significant as a senolytic was highlighted in Kirkland’s laboratory (140)
reduction in systemic BPs associated with oral supplementation (Table 1). First, the investigators identified a series of senolytic
of quercetin (137). The weighed mean differences for the transcripts on pre-adipocytes. These included components of
systolic and diastolic BPs were 3.04 mm Hg (p = 0.028) and the ephrin regulating system, ephrin ligands B (EFNB), as
2.63 mm Hg (p < 0.001), respectively (137). These values are well as the plasminogen-activated inhibitor-1 (PAI-1) and a
appreciable considering that the cohorts were largely made up member of the phosphatidylinositol-4,5-bisphosphate 3 kinase
of normotensive subjects. The doses of quercetin ranged from (PI3 K) family, involved in regulating multiple cellular functions
100 to 1,000 mg/day. Interestingly, when using a meta-regression including survival (140). Then, they tested whether drugs that
analysis, the systolic BP-lowering effect was only associated with target any of these gene products would effectively induce
the duration of supplementation, and not the administered dose, apoptosis in radiation-induced senescent human pre-adipocytes
contrarily to the diastolic BP-lowering effects (137). Furthermore, and HUVECs. Of the 46 agents tested, quercetin and dasatinib,
when the RCTs were stratified according to the duration of a non-specific tyrosine kinase inhibitor used for cancer therapy,
supplementation, quercetin had no significant benefit in the were noticeably promising (140). Dasatinib is known to block
subsets of studies lasting <8 weeks. Likewise, the BP values did EFNB-dependent suppression of apoptosis, while quercetin
not differ significantly between the two treatment arms in the inhibits PI3 K, other kinases and PAI-1, from the SERPIN family
subset of trials administering doses <500 mg/day. Altogether, member (140, 192). In contrast to dasatinib, which was more

effective on pre-adipocytes, quercetin preferentially reduced human aortic endothelial cells (HAECs) (141). In their study,
viability of senescent HUVECs (140). Parallel cultures of non- senescence was induced by ox-LDLs. Their results revealed that
senescent HUVECs proliferated 2- to 3-fold in the presence quercetin decreased the expression of senescence-associated β-
of quercetin over the same period of 3 days, indicating that galactosidase and improved cell morphology of HAECs (141).
quercetin’s induction of apoptosis is selective to SCs (140). In The senolytic effect was dose dependent, as 0.3, 1, and 3
addition, the combination of dasatinib and quercetin achieved µmol/L of quercetin improved cells viability by 10.8, 40.9, and
a synergistic effect by selectively killing both senescent pre- 48.9%, respectively (141). Quercetin simultaneously decreased
adipocytes and HUVECs, whom viability was, respectively, ROS generation, also in a concentration-dependent manner.
reduced by ∼70% and ∼50% (140). This suggests that using In addition, transcriptome microarray assays were performed
a mix of senolytics to target a broader range of anti-apoptotic and identified differentially expressed genes in the mRNAs
networks may be a strategy to follow in developing future profile of senescent HAECs treated with quercetin (141). Among
senolytic therapies (189). Used in vivo, the senolytic cocktail them, several were involved in p53 and mammalian target
also reduced the number of p16-positive SCs in fat and liver of rapamycin (mTOR) signaling pathways, NO metabolism,
from old mice (140). After a single 5 day treatment course maintenance of the cytoskeleton, extracellular matrix-receptor
of dasatinib+quercetin, the rodents exhibited an improved left interaction, as well as complement and coagulation cascades,
ventricular ejection fraction (LVEF) and fractional shortening suggesting the potential mechanisms by which quercetin was
with no alteration of cardiac mass, as well as increased smooth effective against ox-LDLs (141). Quercetin also decreased the
muscle vascular reactivity to nitroprusside (140). Similar results genetic expression of AATK, CDKN2A, and IGFBP3 (141). AATK
were obtained by Xu et al.: 20 month-old mice who were is induced during apoptosis, while CDKN2A (p16) is one of the
fed dasatinib+quercetin intermittently for 4 months performed most important senescence markers (141). Interestingly, a high
better at physical endurance tests compared to the control circulating concentration of IGFBP3 was found to be a predictor
group (43). Next, they administered biweekly oral doses of of IHD (196). One can therefore wonder if quercetin could
dasatinib+quercetin to 24 to 27 month-old mice, equivalent to alleviate the risks of IHD in patients by decreasing IGFBP3.
a human age of 75–90 years; compared to the controls, these Clinical trials studying the senolytic effects of quercetin
mice had a 36% higher median post-treatment lifespan and a 65% remain scarce (Table 1). In the first clinical trial of senolytics,
lower mortality hazard (43). This was neither associated with an an intermittent regimen of dasatinib+quercetin (dasatinib: 100
increased physical morbidity nor an increased age-related disease mg/day, quercetin: 1,250 mg/day, 3 days/week over 3 weeks)
burden (43). In addition, in ApoE−/− mice fed with a high- improved physical tolerance, but not pulmonary function, in
fat diet, dasatinib+quercetin given once monthly for 3 months patients with idiopathic pulmonary fibrosis, a fatal senescence-
was shown to decrease aortic calcifications and increase vascular associated disease (197). Another open label pilot study was
reactivity (193). When used alone, quercetin increased the conducted by Hickson et al. in 9 adults aged 50–80 years with
density of sirtuin 1 (Sirt1) in aorta of ApoE−/− mice (141). Sirt1 diabetic kidney disease (142). The patients received a 3 day oral
functions as a nicotinamide adenosine dinucleotide (NAD+)- treatment regimen with dasatinib 100 mg daily and quercetin
dependent deacetylase and is involved in genomic stability, basal 500 mg bid. Eleven days after treatment completion, there was
level autophagy and cell survival (194). Sirt1 was found to delay a significant reduction in the number of adipose tissue SCs and
both replicative and stress-induced senescence (194). circulating SASP factors, including IL-1α, IL-6, MMP-9, and
Hwang et al. conducted in vitro experiments with adult MMP-12, accompanied by an increase of adipocyte progenitors,
human coronary artery endothelial cells (HCAEC) from three suggesting a selective cytotoxic effect for SCs (142). These results
deceased female donors using replicative senescence as a relevant are in agreement with a previous in vitro study performed on
model for human arterial aging (195). Contrary to the previous human omental tissue resected during gastric bypass surgery
results reported in HUVECs (140), their findings showed that (43). The surgical explants treated with a dasatinib+quercetin
quercetin induces death in both early (non-senescent) and late- medium for 48 h had significantly less SCs and a lower secretion
passage (senescent) HCAECs, without any selectivity for the of SASP components compared to the explants treated with a
latter (195). Quercetin’s cytotoxicity was evident in all three vehicle (43). To the best of our knowledge, no clinical trial has
donors at a concentration of 10 µM, which was half the amount yet examined the senolytic effects of quercetin on endothelial
used with HUVECs (140). Late-passage cells were more sensitive dysfunction in humans, in the context of CVD.
to quercetin’s toxic effects as their relative cell abundance
was already significantly decreased at a concentration of 6 µM Myocardial Protective Effects of Quercetin
(195). Their study also investigated hyperoside, also known as The beneficial effects of quercetin on dyslipidemia, hypertension,
quercetin 3-D-galactoside, as an alternative to quercetin (195). senescence and other risk factors can be seen as a primary
Hyperoside is a natural derivative of quercetin produced by St. prevention measure against endothelial dysfunction. Once the
John’s Wort and structurally identical except for a galactoside endothalial dysfunction has resulted in an adverse cardiac event,
group attached in position 3 (Figure 2) (195). In contrast to secondary and tertiary prevention strategies become crucial in
quercetin, hyperoside had no significant cytotoxicity to either order to reduce the progression of the disease and its impacts
proliferating or late-passage HCAECs but was unable to display on patients’ quality of life. One of the most striking examples
any senolytic activity (195). A second in vitro model of an adult is myocardial ischemia. In the latter, dysfunctional endothelial
human vasculature model was investigated by Jiang et al. using cells of the coronary arteries induce a local disturbance

in other cell lines, including cardiomyocytes and fibroblasts paradoxically increases the degree of myocardial damage (200).
(198). They trigger a host response which includes increased As restoration of the circulation allows blood to reach cells that
oxidative stress, calcium imbalance, as well as cytokine, platelets, were previously subjected to ischemia, sudden availibility of
and leukocytes activation (198). This endothelial dysfunction oxygen leads to a burst in the generation of ROS, mainly deriving
is also a critical mediator of myocardial dysfunction after from the Fenton reaction, NOX, and xanthine oxidase (XO)
reperfusion (198). In response, many pathological adaptations (200). These redox reactions lead to formation of oxygen radicals,
occur, such as increased extracellular matrix deposition leading lipid peroxidation, calcium overload, activation of inflammatory
to myocardial interstitial fibrosis, changes in the myocardial cascades, and apoptosis, which propagate and cause myocardial
cell morphology, and eventually, ventricular dilatation (199). damage even distant to the original site of insult (200). This has
The latter, called “ventricular remodeling” is detrimental to important clinical implications as it limits the benefits of current
ventricular compliance and contractility (199). Clinically, it revascularization therapies such as thrombolysis, angioplasty or
translates into debilitating conditions, ranging from stable coronary artery bypass surgery (200). A number of studies based
angina to myocardial infarction and heart failure. In addition, on the rodent models of transient myocardial infarction have
experimental data showed that endothelial dysfunction correlates suggested that quercetin attenuates MIRI by interfering with
with the degree of myocardial injury, both from the ischemic several of these pathways (Figure 4).
and reperfusion insults (198). These observations suggest that First, quercetin has well-documented antioxidant properties.
quercetin’s ability to minimize myocardial injury following an Thanks to its chemical structure (Figure 2), it is able to
ischemic event may be, at least partly, mediated by its effects on directly scavenge free radicals such as superoxide, hydrogen
the endothelium. peroxide, peroxyl, and hydroxyl radicals (45). Quercetin can
Many in vivo and ex vivo murine studies have shown both also reduce the formation of ROS by inhibiting NOX and
functional and structural benefits of exposing myocardium to XO, decreasing the activity of cyclooxygenase and LOX, as
quercetin in an acute ischemic setting (143–153) (Table 1). well as regulating the activity of intracellular signaling cascades
These studies used rodent models in which transient myocardial involved in inflammatory reactions (53). Chemical studies
injury was induced by ISO injections, surgical occlusion of revealed that quercetin can reversibly inhibit XO-catalyzed uric
the left coronary artery (LAD) or interruption of Langendorff acid and superoxide radicals formation in a double-displacement
perfusion (123, 124, 130, 131, 134–136, 178–181). Quercetin reaction (201, 202). However, results of in vivo studies remain
was either given as an oral gavage, an intravenous or controversial (203). In a hyperuricemic mouse model, quercetin
intraperitoneal infusion (123, 124, 130, 131, 134–136, 178– given orally at 100 mg/kg for 1 to 7 consecutive days reduced
181). Measured functional hemodynamic parameters included serum urate levels and XO hepatic activity in a concentration-
left ventricular end-diastolic pressure (LVEDP), left ventricular dependent manner (204). In another study using the same model,
systolic pressure (LVSP) and maximal ratio of pressure a 7 day treatment of 400 mg/kg orally administered quercetin
change during isovolumetric contraction (peak dP/dt). While failed to reduce both serum urate levels and XO expression (205).
myocardial ischemia systematically decreased LVSP and peak In a rabbit model of surgically-induced MIRI, an intravenous
dP/dt, and increased LVEDP, this effect was counteracted injection of quercetin given 5 min before ligation attenuated the
by quercetin (143–147). Liu et al. used echocardiography in enzymatic activity of NOX2 expressed in endothelial cells (206).
mice to estimate left ventricular function (148). They showed On the other hand, quercetin acts as a chelating agent. It can
that quercetin significantly slowed the decline in LVEF and inhibit the Fenton reaction by interfering with ferrous iron (207).
fractional shortening compared with the control group (148). It can also bind to zinc and facilitate zinc trafficking into cells
On macroscopic examination, treatment with quercetin induced (208), which in turn functions as an antioxidant (209). Lipid
a significant reduction of myocardial infarct size on triphenyl peroxidation is the process by which unsaturated fatty acids
tetrazolium chloride (TTC) staining (149–151). This was further are converted to lipid peroxyl radicals by hydrogen oxidation,
supported by lower levels of serum creatine kinase (CK), which, in turn, extract hydrogen from other fatty acid molecules
CK-MB, cardiac troponin T and lactate dehydrogenase, all to create more free radicals (210). Some studies reported that
enzymatic markers of myocardial insult (144, 147–149, 151–155). quercetin offers a protection against lipid peroxidation chain
Histopathological examinations also revealed lower infiltration reaction by neutralizing peroxyl radicals and by binding to
of leukocytes to the site of infarction, less edema and overall transition metal ions, catalyzers of lipid peroxidation (154, 211,
maintained tissue architecture (149, 152, 153). All these findings 212). Finally, quercetin pretreatment was shown to decrease the
are in favor of a preservation of cardiomyocytes’ membrane content of malondialdehyde (MDA), a mutagenic product of lipid
integrity and global improvement in myocardial function after peroxidation chain reaction, and to potentiate the activity of
exposure with quercetin. Interestingly, these cardioprotective superoxide dismutase (SOD) and glutathione peroxidase (GSH-
effects were observed whether quercetin was administered before Px), two most important antioxidases in cardiomyocytes (144,
induction of ischemia or during reperfusion. This suggests 147, 148, 152, 213, 214). All these properties allow quercetin to
that quercetin may have both ischemic preconditioning and slow down the domino effects of free radical injury in MIRI.
postconditioning capacities. With myocardial ischemia and MIRI, there is a shift toward
Although timely reperfusion is essential for myocardial a pro-inflammatory and pro-apoptotic phenotype caused by
salvage, it is accompanied by a stress reaction known as an increased secretion of cytokines (200). As seen previously,
“myocardial ischemia-reperfusion injury” (MIRI), which quercetin was shown to significantly repress this inflammatory

FIGURE 4 | Schematic representation of the multistep mechanisms of quercetin to mitigate myocardial ischemic reperfusion injury. XO, xanthine oxidase; NOX,
NADPH oxidase.
cascade, both in vivo and in vitro (95). The pro-inflammatory gamma (PPAR-γ) further supports the targetting of NFκB
response is further exacerbated by activation of NFκB, which is activation (148). Several reports revealed that PPAR-γ, a ligand-
a pivot transcription factor in promoting cytokine expression. activated nuclear transcription factor, could suppress the signal
Enhanced NFκB signaling induces a positive feedback, which transduction of NFκB pathway in vascular diseases (216). A
further prompts inflammasome assembly (35). NFκB can be study demonstrated that mice with transient LAD ligation that
activated through the interaction of high mobility group received a 10 day pre-treatment of quercetin had a significantly
box-1 (HMGB1) with toll-like receptors (TLRs) located in higher number of PPAR-γ positive myocardial cells (148). The
cardiomyocytes (215). HMGB1 has been found to be released authors also found that quercetin partially reversed the effects
by necrotic cardiomyocytes under ischemic conditions and of a PPAR-γ inhibitor, GW9662, compared to non-quercetin-
may serve as an early mediator of inflammation following treated mice, with an associated improvement in LVEF, fractional
MIRI (215). Western blot analyses revealed a strong activation shortening and cardiac biomarkers (148). Lastly, quercetin was
of the HMGB1/TLR/NFκB pathway in heart tissues after shown to protect against calcium overload. Elevated intracellular
ischemic/reperfusion stimulation in LAD ligated rats (151). Ca2+ is involved in the deleterious biochemical and functional
Treatment with quercetin significantly inhibited expression changes accompanying MIRI (217). In vitro, quercetin decreased
of HMGB1 and TLR4 (151, 153). In addition, up-regulation Ca2+ -dependent cell death when added to H9C2 cardiomyocyte
by quercetin of peroxisome proliferation-activated receptor 30 min before application of H2 O2 -induced oxidative stress

(218). Furthermore, the downstream Ca2+ activated calpain hypertension (227, 228) or cardiac and renal fibrosis (229,
pathways may lead to contractile dysfunction and cytoskeleton 230). The best-studied mediator of EndoMT is TGF-β (231).
damage (219). Increased calpain activity has been reported The latter can induce EndoMT either directly, through both
as an aggravating factor in myocardial infarction (219). Oral Smad-dependent and Smad-independent pathways (232, 233),
quercetin (50 mg/kg) pre-treatment of Wistar rats exposed to or indirectly, through ET-1 (234, 235), CAV-1 (236), or NFκB
an ISO-induced myocardial infarction downregulated the genetic (151, 153, 237).
expression of calpain 1 and 2, protecting the myocardium from Strong lines of evidence support the cross-links between
their overactivity (152). This cardioprotective effect was also endothelial dysfunction, atherosclerosis, hypertension,
supported by a reduction of CK-MB and cardiac troponin T senescence and EndoMT (228, 238–241). Targeting EndoMT
in quercetin-treated rats compared to the control group (152). opens therefore a new therapeutic avenue against CVD. However,
Another in vivo study found that quercetin prevented inhibition contrarily to the other players of endothelial dysfunction, few
of the sodium-potassium and the calcium pumps caused by studies specifically looked at the potential contribution of
myocardial infarction (149). quercetin. In their study performed in vitro, Huang et al.
Despite extensive experimental data suggesting that quercetin showed that quercetin effectively inhibited TGF-β1-induced
can attenuate MIRI, very few trials have explored the use of human pulmonary arterial endothelial cells proliferation and
quercetin for the treatment of myocardial ischemia in humans. transdifferentiation (242). This suggests that quercetin may be
In the study done by Chekalina et al., 30 out of 85 patients with a potential antagonist for a pathogenic model of pulmonary
stable angina on optimal medical therapy were given quercetin at artery hypertension secondary to pulmonary arterial endothelial
a daily dose of 120 mg for 2 months (156). The quercetin patients cells excessive growth. Moreover, as discussed in previous
had lower levels of IL-1β and TNF-α compared to the control sections, experiments done outside the scope of EndoMT have
group (156). An open-label clinical trial conducted in Ukraine demonstrated that quercetin can downregulate ET-1 (134, 135),
studied the administration of intravenous quercetin (Corvitin) CAV-1 (118), and NFκB, which are all mediators of EndoMT.
over 10 days in patient admitted with an acute myocardial Other studies explored the effects of quercetin on a similar
infarction and heart failure symptoms. After 3 days, there was process as EndoMT but involving epithelial cells, hence the name
a significant improvement in their profile of cardiac biomarkers “epithelial-to-mesenchymal transition” (EMT). In human retinal
and LVEF (157). Altogether, these clinical data suggest that pigment epithelial cells (ARPE-19) exposed to TGF-β1, quercetin
quercetin has potential cardioprotective effects, and form a suppressed proliferation, migration, and collagen I secretion
solid foundation for a potential application of quercetin in (243). It also downregulated EMT-related markers such as alpha-
the prevention of IHD and its complications. This hypothesis smooth muscle actin and N-cadherin; conversely, it upregulated
remains to be tested in large clinical trials. the expression of tight junction proteins and epithelial-cadherin
(243). In addition, quercetin inhibited Smad2/3 phosphorylation
and translocation of Smad4, suggesting that the progression
ENDOTHELIAL-TO-MESENCHYMAL of EMT in ARPE-19 cells was reversed via the Smad pathway
TRANSITION: A LESS EXPLORED PLAYER (243). Incubation with quercetin also reduced EMT in mammary
IN ENDOTHELIAL DYSFUNCTION carcinoma and prostate cancer cell lines (244, 245). Together,
these results support a role for quercetin against EndoMT
In the late 1990’s, endothelial cells were found to undergo and EMT. However, despite multiple similarities between the
a highly dynamic process of dedifferentiation known as two processes, including canonical TGF-β signaling as their
endothelial-to-mesenchymal transition (EndoMT) (220). During driving force (246), more research in EndoMT models is needed
EndoMT, endothelial cells progressively acquire a wide spectrum to further confirm the efficacy of quercetin in targeting its
of phenotypes characteristic of multipotent cells (221). This trigger mechanisms.
phenotype switch involves a reduced expression of distinctive
endothelial cells markers such as von Willebrand factor, vascular
endothelial-cadherin or CD31/PECAM-1 and an increased DISCUSSION
expression of mesenchymal cells markers such as alpha-smooth
muscle actin, vimentin and N-cadherin (220, 222). Similar to The magnitude of the role of endothelial dysfunction in
senescence, EndoMT is a double-edged sword. EndoMT-derived CVD is well-established. Many pathophysiological processes are
cells exhibit hallmarks of invasive cells through cytoskeletal involved, and they contribute to each other in a feedback manner,
reorganization, increased ECM production, loss of cellular as seen with the triad of vascular senescence, hypertension and
adhesion and resultant enhanced migratory potential (223, 224). atherosclerosis. This also means that each pathway is a potential
This process is critical in the developing embryo where it was target for alleviating endothelial dysfunction. Numerous drugs
shown to generate vasculogenesis and the cardiac cushions for are already available to effectively treat dyslipidemia and
valve development (225). EndoMT was also shown to contribute hypertension. In comparison, anti-senescence therapy is only a
to wound healing (226). However, when triggered under certain nascent yet promising research field. Development of senolytic
pathological conditions such as inflammation or shear-stress drugs would bring a conceptual change that an aging vessel is
injuries, EndoMT can give rise to cancer progression (224), not an immutable process. On the other hand, an important
fibrodysplasia ossificans progressive (221), pulmonary arterial clinical consequence of endothelial dysfunction is manifested in

FIGURE 5 | Schematic representation of the endothelial and, by extension, myocardial protective effects of quercetin. These allow quercetin to act as a primary,
secondary and tertiary preventive measure against cardiovascular diseases. AATK: apoptosis-associated tyrosine kinase; ACE: angiotensin-converting enzyme; AngII,
angiotensin II; BK, big K, large-conductance Ca2+ -sensitive K+ channels; CAV-1, caveolin-1; CDKN2A, p16, cyclin-dependent kinase inhibitor 2A; CK-MB, creatinine
kinase-MB; EndoMT, endothelial-to-mesenchymal transition; ET-1, endothelin-1; IGFBP3, insulin-like growth factor binding protein-3; eNOS, endothelial nitric oxide
synthase; NFκB, nuclear factor-kappa B; NO, nitric oxide; ox-LDLs, oxidized low density lipoproteins; Fyn, Src family 59 kDa non-receptor protein tyrosine-kinase;
LAT, linker for activation of T cells; LTCCs, L-type Ca2+ channels; LVEDP, left ventricular end-diastolic pressure; LVEF, left ventricular ejection fraction; LVSP, left
ventricular systolic pressure; MMPs, matrix metalloproteases; PAI-1, plasminogen-activated inhibitor-1; PCSK9, proprotein convertase subtilisin/kexin type 9; PI3 K,
phosphatidylinositol-4,5-bisphosphate 3 kinase; PLCγ2, phospholipase Cγ2; SCFAs, short-chain fatty acids; ROS, reactive oxygen species; SASP,
senescence-associated secretory phenotype; SIRT1, sirtuin-1, nicotinamide adenine dinucleotide [NAD(+)]-dependent protein deacetylase; SOD, superoxide
dismutase; TGF-β, transforming growth factor beta; VGKCs, voltage-gated K+ channels.
IHD. The burden of myocardial ischemia has been improved While this review has focused on conditions originating
with more timely and effective reperfusion strategies such as from a diseased endothelial layer, prevention of endothelial
angioplasty, bypass surgery, antiplatelet, and antithrombotic dysfunction can be achieved by intervening beyond the
agents used to restore the patency of infarct-related coronary endothelium itself. Indeed, endothelial dysfunction is undeniably
arteries. However, at present, there is still no effective therapy associated with the remaining entities of the metabolic
to prevent MIRI. In this review, we have described mechanistic, syndrome: obesity and insulin resistance (247–251). Their
experimental and clinical evidence that suggests quercetin can role as independent risk factors for CVD merits as much
manifest a wide range of cardioprotective biological activities attention as hypertension and dyslipidemia (252). In fact, the
(Table 1). Not only does it have anti-hypertensive and anti- increasing incidence of obesity and corresponding rise in type-
atherosclerotic effects, but it also seems to mitigate senescence 2 diabetes are further challenging the prevention and treatment
and MIRI, two Achilles’ heels in the modern treatment of of CVD (253). The metabolic effects of quercetin against
CVD. Moreover, although still scarce, encouraging data suggest these two conditions have been equally encouraging and were
that quercetin may also act against abnormal EndoMT, an recently reviewed elsewhere (254–258). In addition, it should be
important yet less explored player in endothelial dysfunction. emphasized that, for clarity reasons, the effects of quercetin on
These properties of quercetin form the basis for its potential the various biochemical and biomechanical signaling cascades
benefits against aging-related endothelial dysfunction and involved in endothelial dysfunction were discussed as separate
CVD (Figure 5). entities. However, in reality, senescence, vasomotor dysfunction,

atherosclerosis, EndoMT, inflammation, oxidative stress, and appealing properties might suggest that we should reconsider our
altered endothelial cellular metabolism all interact, cross talk expectations for its potential therapeutic implications. If a defect
and occur simultaneously. The resulting chain reactions create of the endothelium was accountable for a disease, and a drug
a vicious circle, which, once it is established in one person, can could be given which would correct the defect, the disease would
easily multiply their cardiovascular risks. The ability of quercetin obviously be cured. However, drugs that were to act through less
to act as such a versatile multi-target agent against the domino direct principles might still be useful. For example, if quercetin’s
effect of endothelial dysfunction becomes very appealing. It well-established anti-inflammatory and antioxidant effects, albeit
seems to be promising not only in primary prevention, but also less specific, could make the endothelium less vulnerable to injury
in secondary and tertiary prevention against the dysfunctional and senescence, it could potentially reinforce the efficacy of other
coronary endothelium and myocardium exposed to ischemia- cardiovascular agents. Ultimately, managing CVD has never been
reperfusion injuries. about carrying a hammer and treating everything “as if it were a
However, after being studied for two decades and showing nail.” Instead, it revolves around adding different tools to tackle
encouraging in vitro and in vivo results, quercetin still occupies different issues of a large-scale problem.
a modest title as a dietary supplement. This could be explained In conclusion, quercetin represents a promising natural
by a couple of factors. First, quercetin lacks molecular specificity. compound that appears to satisfy all the requirements to
It does not radically block a metabolic pathway nor inhibit develop a nutraceutical against endothelial dysfunction. There
a receptor of interest. Instead, quercetin has a wide variety is a pressing need for well-designed clinical trials that
of biological activities, which makes it difficult to establish a explore its intriguing potential for senolytic therapy and
clear association between its administration and the observed myocardial protection.
positive effects. As a matter of fact, quercetin’s role as a direct
senolytic agent is still open for discussion. Does it selectively
target SCs, or does it improve their clearance by off-target AUTHOR CONTRIBUTIONS
mechanisms such as antioxidant activity? Second, clinical trials
OD, NT-T, and ET designed the project and its main conceptual
using more consistent protocols are needed to consolidate the
ideas. OD performed the research strategy, data collection, data
medical findings attributed to quercetin. Published trials have
analysis and interpretation, drafted the manuscript, and designed
been using various treatment durations, doses and routes of
the figures, with input from all authors. All authors provided
administration, certainly contributing to heterogenous findings.
critical revisions to the article and approved the final version
The considerable variation in bioavailability of quercetin
for publication.
among individuals might result in subtherapeutic plasma
concentrations, especially when using lower doses. Furthermore,
in vitro experiments most often administered a hit-and-run FUNDING
treatment with quercetin. We could hypothesize that replicating
this regimen in humans would yield more substantial effects. This work was supported by the Canadian Institutes of Health
Lastly, to quote Samuel Butler, “medicine is not practiced as an Research [PJT 166110 and PJT 162446 to ET]; and the
art of drawing sufficient conclusions from insufficient premises.” Foundation of the Montreal Heart Institute [ET and MC]. PM is
In the case of quercetin, the absence of its medical use despite its a post-doctoral scholar from the Fonds de la recherche du Québec.
REFERENCES 7. Zuchi C, Ambrosio G, Luscher TF, Landmesser U. Nutraceuticals in

cardiovascular prevention: lessons from studies on endothelial function.
1. Daiber A, Steven S, Weber A, Shuvaev VV, Muzykantov VR, Laher I, et Cardiovasc Ther. (2010) 28:187–201. doi: 10.1111/j.1755-5922.2010.00165.x
al. Targeting vascular (endothelial) dysfunction. Br J Pharmacol. (2017) 8. Mozaffarian D, Wu JHY. Flavonoids, dairy foods, and cardiovascular and
174:1591–619. doi: 10.1111/bph.13517 metabolic health: a review of emerging biologic pathways. Circ Res. (2018)
2. Thorin E. Life [ageing] is like riding a bicycle. To keep your [coronary 122:369–84. doi: 10.1161/CIRCRESAHA.117.309008
and heart] balance you must keep moving. J Physiol. (2017) 595:3701– 9. RusznyÁK ST, Szent-GyÖRgyi A. Vitamin P: flavonols as vitamins. Nature.
2. doi: 10.1113/JP274297 (1936) 138:27. doi: 10.1038/138027a0
3. Thorin E, Thorin-Trescases N. Vascular endothelial ageing, heartbeat after 10. Patel RV, Mistry BM, Shinde SK, Syed R, Singh V, Shin HS. Therapeutic
heartbeat. Cardiovasc Res. (2009) 84:24–32. doi: 10.1093/cvr/cvp236 potential of quercetin as a cardiovascular agent. Eur J Med Chem. (2018)
4. Matsuzawa Y, Lerman A. Endothelial dysfunction and coronary artery 155:889–904. doi: 10.1016/j.ejmech.2018.06.053
disease: assessment, prognosis, and treatment. Coron Artery Dis. (2014) 11. Rosen GM, Tsai P, Pou S. Mechanism of free-radical generation by nitric
25:713–24. doi: 10.1097/MCA.0000000000000178 oxide synthase. Chem Rev. (2002) 102:1191–200. doi: 10.1021/cr010187s
5. Mensah GA, Wei GS, Sorlie PD, Fine LJ, Rosenberg Y, Kaufmann PG, et al. 12. Hadi HA, Carr CS, Al Suwaidi J. Endothelial dysfunction: cardiovascular risk
Decline in cardiovascular mortality: possible causes and implications. factors, therapy, and outcome. Vasc Health Risk Manag. (2005) 1:183–98.
Circ Res. (2017) 120:366–80. doi: 10.1161/CIRCRESAHA.116.30 13. Bonetti PO, Lerman LO, Lerman A. Endothelial dysfunction: a marker
9115 of atherosclerotic risk. Arterioscler Thromb Vasc Biol. (2003) 23:168–
6. Alfaras I, Di Germanio C, Bernier M, Csiszar A, Ungvari Z, Lakatta EG, et 75. doi: 10.1161/01.atv.0000051384.43104.fc
al. Pharmacological strategies to retard cardiovascular aging. Circ Res. (2016) 14. Konukoglu D, Uzun H. Endothelial dysfunction and hypertension. Adv Exp
118:1626–42. doi: 10.1161/CIRCRESAHA.116.307475 Med Biol. (2017) 956:511–40. doi: 10.1007/5584_2016_90

15. Gimbrone MA Jr., Garcia-Cardena G. Endothelial cell dysfunction 36. Caland L, Labbe P, Mamarbachi M, Villeneuve L, Ferbeyre G, Noly PE, et al.
and the pathobiology of atherosclerosis. Circ Res. (2016) 118:620– Knockdown of angiopoietin-like 2 induces clearance of vascular endothelial
36. doi: 10.1161/CIRCRESAHA.115.306301 senescent cells by apoptosis, promotes endothelial repair and slows
16. Warboys CM, Amini N, de Luca A, Evans PC. The role of blood flow in atherogenesis in mice. Aging. (2019) 11:3832–50. doi: 10.18632/aging.102020
determining the sites of atherosclerotic plaques. F1000 Med Rep. (2011) 37. Noly PE, Labbe P, Thorin-Trescases N, Fortier A, Nguyen A, Thorin E, et
3:5. doi: 10.3410/M3-5 al. Reduction of plasma angiopoietin-like 2 after cardiac surgery is related to
17. Forstermann U, Munzel T. Endothelial nitric oxide synthase in tissue inflammation and senescence status of patients. J Thorac Cardiovasc
vascular disease: from marvel to menace. Circulation. (2006) Surg. (2019) 158:792–802 e5. doi: 10.1016/j.jtcvs.2018.12.047
113:1708–14. doi: 10.1161/CIRCULATIONAHA.105.602532 38. Voghel G, Thorin-Trescases N, Mamarbachi AM, Villeneuve L, Mallette
18. Yang YM, Huang A, Kaley G, Sun D. eNOS uncoupling and endothelial FA, Ferbeyre G, et al. Endogenous oxidative stress prevents telomerase-
dysfunction in aged vessels. Am J Physiol Heart Circ Physiol. (2009) dependent immortalization of human endothelial cells. Mech Ageing Dev.
297:H1829–36. doi: 10.1152/ajpheart.00230.2009 (2010) 131:354–63. doi: 10.1016/j.mad.2010.04.004
19. Hamasaki S, Al Suwaidi J, Higano ST, Miyauchi K, Holmes DR Jr., et al. 39. Childs BG, Durik M, Baker DJ, van Deursen JM. Cellular senescence in
Attenuated coronary flow reserve and vascular remodeling in patients with aging and age-related disease: from mechanisms to therapy. Nat Med. (2015)
hypertension and left ventricular hypertrophy. J Am Coll Cardiol. (2000) 21:1424–35. doi: 10.1038/nm.4000
35:1654–60. doi: 10.1016/s0735-1097(00)00594-5 40. Krouwer VJ, Hekking LH, Langelaar-Makkinje M, Regan-Klapisz E,
20. Ludmer PL, Selwyn AP, Shook TL, Wayne RR, Mudge GH, Alexander Post JA. Endothelial cell senescence is associated with disrupted cell-
RW, et al. Paradoxical vasoconstriction induced by acetylcholine in cell junctions and increased monolayer permeability. Vasc Cell. (2012)
atherosclerotic coronary arteries. N Engl J Med. (1986) 315:1046– 4:12. doi: 10.1186/2045-824X-4-12
51. doi: 10.1056/NEJM198610233151702 41. Freitas-Rodriguez S, Folgueras AR, Lopez-Otin C. The role
21. Reddy KG, Nair RN, Sheehan HM, Hodgson JM. Evidence that selective of matrix metalloproteinases in aging: tissue remodeling and
endothelial dysfunction may occur in the absence of angiographic or beyond. Biochim Biophys Acta Mol Cell Res. (2017) 1864(Pt.
ultrasound atherosclerosis in patients with risk factors for atherosclerosis. A):2015–25. doi: 10.1016/j.bbamcr.2017.05.007
J Am Coll Cardiol. (1994) 23:833–43. doi: 10.1016/0735-1097(94)90627-0 42. Kang TW, Yevsa T, Woller N, Hoenicke L, Wuestefeld T, Dauch D, et
22. Davignon J, Ganz P. Role of endothelial dysfunction in al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer
atherosclerosis. Circulation. (2004) 109(Suppl. 1):III27– development. Nature. (2011) 479:547–51. doi: 10.1038/nature10599
32. doi: 10.1161/01.CIR.0000131515.03336.f8 43. Xu M, Pirtskhalava T, Farr JN, Weigand BM, Palmer AK, Weivoda MM, et
23. Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. al. Senolytics improve physical function and increase lifespan in old age. Nat
Exp Cell Res. (1961) 25:585–621. doi: 10.1016/0014-4827(61)90192-6 Med. (2018) 24:1246–56. doi: 10.1038/s41591-018-0092-9
24. Gorgoulis V, Adams PD, Alimonti A, Bennett DC, Bischof O, Bishop C, 44. Kohn JC, Lampi MC, Reinhart-King CA. Age-related vascular
et al. Cellular senescence: defining a path forward. Cell. (2019) 179:813– stiffening: causes and consequences. Front Genet. (2015)
27. doi: 10.1016/j.cell.2019.10.005 6:112. doi: 10.3389/fgene.2015.00112
25. Paez-Ribes M, Gonzalez-Gualda E, Doherty GJ, Munoz-Espin D. Targeting 45. Xu D, Hu MJ, Wang YQ, Cui YL. Antioxidant activities of quercetin
senescent cells in translational medicine. EMBO Mol Med. (2019) and its complexes for medicinal application. Molecules. (2019)
11:e10234. doi: 10.15252/emmm.201810234 24:1123. doi: 10.3390/molecules24061123
26. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The 46. Panche AN, Diwan AD, Chandra SR. Flavonoids: an overview. J Nutr Sci.
hallmarks of aging. Cell. (2013) 153:1194–217. doi: 10.1016/j.cell.2013.05.039 (2016) 5:e47. doi: 10.1017/jns.2016.41
27. Acosta JC, O’Loghlen A, Banito A, Guijarro MV, Augert A, Raguz S, et al. 47. Peterson JJ, Dwyer JT, Jacques PF, McCullough ML. Improving the
Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell. estimation of flavonoid intake for study of health outcomes. Nutr Rev. (2015)
(2008) 133:1006–18. doi: 10.1016/j.cell.2008.03.038 73:553–76. doi: 10.1093/nutrit/nuv008
28. Kuilman T, Michaloglou C, Vredeveld LC, Douma S, van Doorn 48. Magar RT, Sohng JK. A review on structure, modifications and structure-
R, Desmet CJ, et al. Oncogene-induced senescence relayed by an activity relation of quercetin and its derivatives. J Microbiol Biotechnol. (2020)
interleukin-dependent inflammatory network. Cell. (2008) 133:1019– 30:11–20. doi: 10.4014/jmb.1907.07003
31. doi: 10.1016/j.cell.2008.03.039 49. Lesjak M, Beara I, Simin N, Pintać D, Majkić T, Bekvalac K, et al. Antioxidant
29. Lopes-Paciencia S, Saint-Germain E, Rowell MC, Ruiz AF, Kalegari and anti-inflammatory activities of quercetin and its derivatives. J Funct
P, Ferbeyre G. The senescence-associated secretory phenotype and its Foods. (2018) 40:68–75. doi: 10.1016/j.jff.2017.10.047
regulation. Cytokine. (2019) 117:15–22. doi: 10.1016/j.cyto.2019.01.013 50. Liu X, Raghuvanshi R, Ceylan FD, Bolling BW. Quercetin and its metabolites
30. Storer M, Mas A, Robert-Moreno A, Pecoraro M, Ortells MC, Di inhibit recombinant human angiotensin-converting enzyme 2 (ACE2)
Giacomo V, et al. Senescence is a developmental mechanism that activity. J Agric Food Chem. (2020) 68:13982–9. doi: 10.1021/acs.jafc.0c05064
contributes to embryonic growth and patterning. Cell. (2013) 155:1119– 51. Santos AC, Uyemura SA, Lopes JL, Bazon JN, Mingatto FE, Curti C. Effect
30. doi: 10.1016/j.cell.2013.10.041 of naturally occurring flavonoids on lipid peroxidation and membrane
31. Jun JI, Lau LF. The matricellular protein CCN1 induces fibroblast senescence permeability transition in mitochondria. Free Radic Biol Med. (1998)
and restricts fibrosis in cutaneous wound healing. Nat Cell Biol. (2010) 24:1455–61. doi: 10.1016/s0891-5849(98)00003-3
12:676–85. doi: 10.1038/ncb2070 52. Srinivas K, King JW, Howard LR, Monrad JK. Solubility and
32. Feng T, Meng J, Kou S, Jiang Z, Huang X, Lu Z, et al. CCN1-induced cellular solution thermodynamic properties of quercetin and quercetin
senescence promotes heart regeneration. Circulation. (2019) 139:2495– dihydrate in subcritical water. J Food Eng. (2010) 100:208–
8. doi: 10.1161/CIRCULATIONAHA.119.039530 18. doi: 10.1016/j.jfoodeng.2010.04.001
33. Ritschka B, Storer M, Mas A, Heinzmann F, Ortells MC, Morton 53. Li Y, Yao J, Han C, Yang J, Chaudhry MT, Wang S, et al.
JP, et al. The senescence-associated secretory phenotype induces Quercetin, inflammation and immunity. Nutrients. (2016)
cellular plasticity and tissue regeneration. Genes Dev. (2017) 8:167. doi: 10.3390/nu8030167
31:172–83. doi: 10.1101/gad.290635.116 54. Rahman HS, Othman HH, Hammadi NI, Yeap SK, Amin KM, Abdul
34. Franceschi C, Bonafe M, Valensin S, Olivieri F, De Luca M, Ottaviani E, et al. Samad N, et al. Novel drug delivery systems for loading of natural plant
Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N extracts and their biomedical applications. Int J Nanomed. (2020) 15:2439–
Y Acad Sci. (2000) 908:244–54. doi: 10.1111/j.1749-6632.2000.tb06651.x 83. doi: 10.2147/IJN.S227805
35. Jia G, Aroor AR, Jia C, Sowers JR. Endothelial cell senescence in aging- 55. Wu LD, Enjiang Y, Xiaona C, Xinguo W, Zhengzan Z, Lingzhen Q, et al.
related vascular dysfunction. Biochim Biophys Acta Mol Basis Dis. (2019) Enhancing oral bioavailability of quercetin using novel soluplus polymeric
1865:1802–9. doi: 10.1016/j.bbadis.2018.08.008 micelles. Nanoscale Res Lett. (2014) 9:1–11. doi: 10.1186/1556-276X-9-684

56. Zhang L, Dong M, Guangyong X, Yuan T, Tang H, Wang Y. 75. D’Andrea G. Quercetin: a flavonol with multifaceted
Metabolomics reveals that dietary ferulic acid and quercetin therapeutic applications? Fitoterapia. (2015) 106:256–
modulate metabolic homeostasis in rats. J Agric Food Chem. (2018) 71. doi: 10.1016/j.fitote.2015.09.018
66:1723–31. doi: 10.1021/acs.jafc.8b00054 76. Juzwiak S, Wojcicki J, Mokrzycki K, Marchlewicz M, Bialecka M, Wenda-
57. Tanaka S, Oyama M, Nishikawa M, Ikushiro S, Hara H. Simultaneous Rozewicka L, et al. Effect of quercetin on experimental hyperlipidemia and
collection of the portal and superior vena cava blood in conscious rats atherosclerosis in rabbits. Pharmacol Rep. (2005) 57:604–9.
defined that intestinal epithelium is the major site of glucuronidation, but not 77. Hayek T, Fuhrman B, Vaya J, Rosenblat M, Belinky P, Coleman
sulfation and methylation, of quercetin. Biosci Biotechnol Biochem. (2018) R, et al. Reduced progression of atherosclerosis in apolipoprotein E-
82:2118–29. doi: 10.1080/09168451.2018.1515615 deficient mice following consumption of red wine, or its polyphenols
58. Moon YJ, Wang L, DiCenzo R, Morris ME. Quercetin pharmacokinetics in quercetin or catechin, is associated with reduced susceptibility of LDL to
humans. Biopharm Drug Dispos. (2008) 29:205–17. doi: 10.1002/bdd.605 oxidation and aggregation. Arterioscler Thromb Vasc Biol. (1997) 17:2744–
59. Kaushik D, O’Fallon K, Clarkson PM, Dunne CP, Conca KR, 52. doi: 10.1161/01.atv.17.11.2744
Michniak-Kohn B. Comparison of quercetin pharmacokinetics 78. Li SS, Cao H, Shen DZ, Chen C, Xing SL, Dou FF, et al. Effect
following oral supplementation in humans. J Food Sci. (2012) of quercetin on atherosclerosis based on expressions of ABCA1, LXR-
77:H231–8. doi: 10.1111/j.1750-3841.2012.02934.x alpha and PCSK9 in ApoE(-/-) mice. Chin J Integr Med. (2020) 26:114–
60. Dabeek WM, Marra MV. Dietary quercetin and kaempferol: bioavailability 21. doi: 10.1007/s11655-019-2942-9
and potential cardiovascular-related bioactivity in humans. Nutrients. (2019) 79. Garelnabi M, Mahini H, Wilson T. Quercetin intake with exercise modulates
11:2288. doi: 10.3390/nu11102288 lipoprotein metabolism and reduces atherosclerosis plaque formation. J Int
61. Boesch-Saadatmandi C, Niering J, Minihane AM, Wiswedel I, Gardeman A, Soc Sports Nutr. (2014) 11:22. doi: 10.1186/1550-2783-11-22
Wolffram S, et al. Impact of apolipoprotein E genotype and dietary quercetin 80. Lu XL, Zhao CH, Yao XL, Zhang H. Quercetin attenuates high fructose
on paraoxonase 1 status in apoE3 and apoE4 transgenic mice. Atherosclerosis. feeding-induced atherosclerosis by suppressing inflammation and apoptosis
(2010) 211:110–3. doi: 10.1016/j.atherosclerosis.2010.02.027 via ROS-regulated PI3K/AKT signaling pathway. Biomed Pharmacother.
62. Egert S, Boesch-Saadatmandi C, Wolffram S, Rimbach G, Muller (2017) 85:658–71. doi: 10.1016/j.biopha.2016.11.077
MJ. Serum lipid and blood pressure responses to quercetin vary in 81. Nie J, Zhang L, Zhao G, Du X. Quercetin reduces atherosclerotic lesions by
overweight patients by apolipoprotein E genotype. J Nutr. (2010) 140:278– altering the gut microbiota and reducing atherogenic lipid metabolites. J Appl
84. doi: 10.3945/jn.109.117655 Microbiol. (2019) 127:1824–34. doi: 10.1111/jam.14441
63. Shimoi K, Nakayama T. Glucuronidase deconjugation in inflammation. 82. Jia Q, Cao H, Shen D, Li S, Yan L, Chen C, et al. Quercetin protects
Methods Enzymol. (2005) 400:263–72. doi: 10.1016/S0076-6879(05)00015-7 against atherosclerosis by regulating the expression of PCSK9, CD36,
64. Elbarbry F, Ung A, Abdelkawy K. Studying the inhibitory PPARgamma, LXRalpha and ABCA1. Int J Mol Med. (2019) 44:893–
effect of quercetin and thymoquinone on human cytochrome 902. doi: 10.3892/ijmm.2019.4263
P450 enzyme activities. Pharmacogn Mag. (2018) 13(Suppl. 83. Xiao L, Liu L, Guo X, Zhang S, Wang J, Zhou F, et al. Quercetin attenuates
4):S895–9. doi: 10.4103/0973-1296.224342 high fat diet-induced atherosclerosis in apolipoprotein E knockout mice:
65. Choi JS, Choi BC, Choi KE. Effect of quercetin on the a critical role of NADPH oxidase. Food Chem Toxicol. (2017) 105:22–
pharmacokinetics of oral cyclosporine. Am J Health Syst Pharm. (2004) 33. doi: 10.1016/j.fct.2017.03.048
61:2406–9. doi: 10.1093/ajhp/61.22.2406 84. Cao H, Jia Q, Shen D, Yan L, Chen C, Xing S, et al. Quercetin has a protective
66. Wang YH, Chao PD, Hsiu SL, Wen KC, Hou YC. Lethal quercetin-digoxin effect on atherosclerosis via enhancement of autophagy in ApoE-/- mice. Exp
interaction in pigs. Life Sci. (2004) 74:1191–7. doi: 10.1016/j.lfs.2003.06.044 Ther Med. (2021) 18:2451–8. doi: 10.3892/etm.2019.7851
67. Andres S, Pevny S, Ziegenhagen R, Bakhiya N, Schafer B, Hirsch-Ernst KI, 85. Wu DN, Guan L, Jiang YX, Ma SH, Sun YN, Lei HT, et al. Microbiome
et al. Safety aspects of the use of quercetin as a dietary supplement. Mol Nutr and metabonomics study of quercetin for the treatment of atherosclerosis.
Food Res. (2018) 62:1700447. doi: 10.1002/mnfr.201700447 Cardiovasc Diagn Ther. (2019) 9:545–60. doi: 10.21037/cdt.2019.12.04
68. Hilliard JJ, Krause HM, Bernstein JI, Fernandez JA, Nguyen V, Ohemeng 86. Zhang M, Xie Z, Gao W, Pu L, Wei J, Guo C. Quercetin regulates
KA, et al. A comparison of active site binding of 4-quinolones and novel hepatic cholesterol metabolism by promoting cholesterol-to-bile acid
flavone gyrase inhibitors to DNA gyrase. Adv Exp Med Biol. (1995) 390:59– conversion and cholesterol efflux in rats. Nutr Res. (2016) 36:271–
69. doi: 10.1007/978-1-4757-9203-4_5 9. doi: 10.1016/j.nutres.2015.11.019
69. Woodward CJ, Deyo ZM, Donahue KE, Deal AM, Hawes EM. 87. Son HY, Lee MS, Chang E, Kim SY, Kang B, Ko H, et al. Formulation
Clinically relevant interaction between warfarin and scuppernongs, a and characterization of quercetin-loaded oil in water nanoemulsion
quercetin containing muscadine grape: continued questions surrounding and evaluation of hypocholesterolemic activity in rats. Nutrients. (2019)
flavonoid-induced warfarin interactions. BMJ Case Rep. (2014) 11:244. doi: 10.3390/nu11020244
2014:bcr2013009608. doi: 10.1136/bcr-2013-009608 88. Kang HJ, Pichiah PBT, Abinaya RV, Sohn HS, Cha YS. Hypocholesterolemic
70. Harwood M, Danielewska-Nikiel B, Borzelleca JF, Flamm GW, Williams effect of quercetin-rich onion peel extract in C57BL/6J mice
GM, Lines TC. A critical review of the data related to the safety of fed with high cholesterol diet. Food Sci Biotechnol. (2016)
quercetin and lack of evidence of in vivo toxicity, including lack of 25:855–60. doi: 10.1007/s10068-016-0141-4
genotoxic/carcinogenic properties. Food Chem Toxicol. (2007) 45:2179– 89. Tian H, Liu Q, Qin S, Zong C, Zhang Y, Yao S, et al. Synthesis and
205. doi: 10.1016/j.fct.2007.05.015 cardiovascular protective effects of quercetin 7-O-sialic acid. J Cell Mol Med.
71. Vickery HB, Nelson EM, Almquist HJ, Elvehjem CA. Term “vitamin (2017) 21:107–20. doi: 10.1111/jcmm.12943
P” recommended to be discontinued. Science. (1950) 112:628. 90. Chang YC, Lee TS, Chiang AN. Quercetin enhances ABCA1 expression and
doi: 10.1126/science.112.2917.628 cholesterol efflux through a p38-dependent pathway in macrophages. J Lipid
72. Hertog MG, Feskens EJ, Hollman PC, Katan MB, Kromhout Res. (2012) 53:1840–50. doi: 10.1194/jlr.M024471
D. Dietary antioxidant flavonoids and risk of coronary heart 91. Ren K, Jiang T, Zhao GJ. Quercetin induces the selective uptake of
disease: the Zutphen Elderly Study. Lancet. (1993) 342:1007– HDL-cholesterol via promoting SR-BI expression and the activation
11. doi: 10.1016/0140-6736(93)92876-u of the PPARgamma/LXRalpha pathway. Food Funct. (2018) 9:624–
73. Haseeb S, Alexander B, Baranchuk A. Wine and cardiovascular 35. doi: 10.1039/c7fo01107e
health: a comprehensive review. Circulation. (2017) 136:1434– 92. Li S, Cao H, Shen D, Jia Q, Chen C, Xing SL. Quercetin
48. doi: 10.1161/CIRCULATIONAHA.117.030387 protects against oxLDLinduced injury via regulation of
74. Sanchez M, Romero M, Gomez-Guzman M, Tamargo J, Perez-Vizcaino ABCAl, LXRalpha and PCSK9 in RAW264.7 macrophages.
F, Duarte J. Cardiovascular effects of flavonoids. Curr Med Chem. (2019) Mol Med Rep. (2018) 18:799–806. doi: 10.3892/mmr.2018.
26:6991–7034. doi: 10.2174/0929867326666181220094721 9048

93. Punithavathi VR, Prince PS. Combined effects of quercetin and alpha- atherosclerosis-related acute aortic syndromes in mice. Int J Mol Sci. (2020)
tocopherol on lipids and glycoprotein components in isoproterenol induced 21:7226. doi: 10.3390/ijms21197226
myocardial infarcted Wistar rats. Chem Biol Interact. (2009) 181:322– 110. Tong F, Liu S, Yan B, Li X, Ruan S, Yang S. Quercetin nanoparticle
7. doi: 10.1016/j.cbi.2009.07.002 complex attenuated diabetic nephropathy via regulating the expression
94. Song L, Xu M, Lopes-Virella MF, Huang Y. Quercetin inhibits matrix level of ICAM-1 on endothelium. Int J Nanomed. (2017) 12:7799–
metalloproteinase-1 expression in human vascular endothelial cells through 813. doi: 10.2147/IJN.S146978
extracellular signal-regulated kinase. Arch Biochem Biophys. (2001) 391:72– 111. Bian Y, Liu P, Zhong J, Hu Y, Zhuang S, Fan K, et al. Quercetin attenuates
8. doi: 10.1006/abbi.2001.2402 adhesion molecule expression in intestinal microvascular endothelial
95. Xue F, Nie X, Shi J, Liu Q, Wang Z, Li X, et al. Quercetin inhibits cells by modulating multiple pathways. Dig Dis Sci. (2018) 63:3297–
LPS-induced inflammation and ox-LDL-induced lipid deposition. Front 304. doi: 10.1007/s10620-018-5221-2
Pharmacol. (2017) 8:40. doi: 10.3389/fphar.2017.00040 112. Tabrizi R, Tamtaji OR, Mirhosseini N, Lankarani KB, Akbari M,
96. Saragusti AC, Ortega MG, Cabrera JL, Estrin DA, Marti MA, Chiabrando Heydari ST, et al. The effects of quercetin supplementation on lipid
GA. Inhibitory effect of quercetin on matrix metalloproteinase 9 profiles and inflammatory markers among patients with metabolic
activity molecular mechanism and structure-activity relationship syndrome and related disorders: a systematic review and meta-analysis
of the flavonoid-enzyme interaction. Eur J Pharmacol. (2010) of randomized controlled trials. Crit Rev Food Sci Nutr. (2020) 60:1855–
644:138–45. doi: 10.1016/j.ejphar.2010.07.001 68. doi: 10.1080/10408398.2019.1604491
97. Scoditti E, Calabriso N, Massaro M, Pellegrino M, Storelli C, Martines 113. Burak C, Wolffram S, Zur B, Langguth P, Fimmers R, Alteheld B, et al.
G, et al. Mediterranean diet polyphenols reduce inflammatory Effect of alpha-linolenic acid in combination with the flavonol quercetin
angiogenesis through MMP-9 and COX-2 inhibition in human on markers of cardiovascular disease risk in healthy, non-obese adults: a
vascular endothelial cells: a potentially protective mechanism in randomized, double-blinded placebo-controlled crossover trial. Nutrition.
atherosclerotic vascular disease and cancer. Arch Biochem Biophys. (2012) (2019) 58:47–56. doi: 10.1016/j.nut.2018.06.012
527:81–9. doi: 10.1016/j.abb.2012.05.003 114. Bojic M, Debeljak Z, Tomicic M, Medic-Saric M, Tomic S. Evaluation
98. Wang L, Wang B, Li H, Lu H, Qiu F, Xiong L, et al. Quercetin, a of antiaggregatory activity of flavonoid aglycone series. Nutr J. (2011)
flavonoid with anti-inflammatory activity, suppresses the development of 10:73. doi: 10.1186/1475-2891-10-73
abdominal aortic aneurysms in mice. Eur J Pharmacol. (2012) 690:133– 115. Boyanov KO, Maneva AI. Influence of platelet aggregation modulators on
41. doi: 10.1016/j.ejphar.2012.06.018 cyclic amp production in human thrombocytes. Folia Med. (2018) 60:241–
99. Ko EY, Nile SH, Jung YS, Keum YS. Antioxidant and antiplatelet potential 7. doi: 10.1515/folmed-2017-0091
of different methanol fractions and flavonols extracted from onion (Allium 116. Beretz A, Stierle A, Anton R, Cazenave JP. Role of cyclic AMP in the
cepa L.). 3 Biotech. (2018) 8:155. doi: 10.1007/s13205-018-1184-4 inhibition of human platelet aggregation by quercetin, a flavonoid that
100. Stainer AR, Sasikumar P, Bye AP, Unsworth AJ, Holbrook LM, Tindall M, potentiates the effect of prostacyclin. Biochem Pharmacol. (1982) 31:3597–
et al. The metabolites of the dietary flavonoid quercetin possess potent 600. doi: 10.1016/0006-2952(82)90581-0
antithrombotic activity, and interact with aspirin to enhance antiplatelet 117. Kobuchi H, Roy S, Sen CK, Nguyen HG, Packer L. Quercetin
effects. TH Open. (2019) 3:e244–58. doi: 10.1055/s-0039-1694028 inhibits inducible ICAM-1 expression in human endothelial
101. Hubbard GP, Wolffram S, Lovegrove JA, Gibbins JM. Ingestion of quercetin cells through the JNK pathway. Am J Physiol. (1999) 277:C403–
inhibits platelet aggregation and essential components of the collagen- 11. doi: 10.1152/ajpcell.1999.277.3.C403
stimulated platelet activation pathway in humans. J Thromb Haemost. (2004) 118. Kamada C, Mukai R, Kondo A, Sato S, Terao J. Effect of quercetin and
2:2138–45. doi: 10.1111/j.1538-7836.2004.01067.x its metabolite on caveolin-1 expression induced by oxidized LDL and
102. Wright B, Moraes LA, Kemp CF, Mullen W, Crozier A, Lovegrove JA, et al. lysophosphatidylcholine in endothelial cells. J Clin Biochem Nutr. (2016)
A structural basis for the inhibition of collagen-stimulated platelet function 58:193–201. doi: 10.3164/jcbn.16-2
by quercetin and structurally related flavonoids. Br J Pharmacol. (2010) 119. Egert S, Bosy-Westphal A, Seiberl J, Kurbitz C, Settler U, Plachta-
159:1312–25. doi: 10.1111/j.1476-5381.2009.00632.x Danielzik S, et al. Quercetin reduces systolic blood pressure and
103. Choi JS, Kang SW, Li J, Kim JL, Bae JY, Kim DS, et al. Blockade of plasma oxidised low-density lipoprotein concentrations in overweight
oxidized LDL-triggered endothelial apoptosis by quercetin and rutin through subjects with a high-cardiovascular disease risk phenotype: a double-
differential signaling pathways involving JAK2. J Agric Food Chem. (2009) blinded, placebo-controlled cross-over study. Br J Nutr. (2009) 102:1065–
57:2079–86. doi: 10.1021/jf803390m 74. doi: 10.1017/S0007114509359127
104. Yang MY, Huang CN, Chan KC, Yang YS, Peng CH, Wang 120. Chopra M, Fitzsimons PE, Strain JJ, Thurnham DI, Howard AN.
CJ. Mulberry leaf polyphenols possess antiatherogenesis effect Nonalcoholic red wine extract and quercetin inhibit LDL oxidation without
via inhibiting LDL oxidation and foam cell formation. J affecting plasma antioxidant vitamin and carotenoid concentrations. Clin
Agric Food Chem. (2011) 59:1985–95. doi: 10.1021/jf103 Chem. (2000) 46(Pt. 1):1162–70. doi: 10.1093/clinchem/46.8.1162
661v 121. Choi S, Ryu KH, Park SH, Jun JY, Shin BC, Chung JH, et al. Direct vascular
105. Yao S, Sang H, Song G, Yang N, Liu Q, Zhang Y, et al. Quercetin protects actions of quercetin in aorta from renal hypertensive rats. Kidney Res Clin
macrophages from oxidized low-density lipoprotein-induced apoptosis by Pract. (2016) 35:15–21. doi: 10.1016/j.krcp.2015.12.003
inhibiting the endoplasmic reticulum stress-C/EBP homologous protein 122. Duarte J, Perez-Palencia R, Vargas F, Ocete MA, Perez-Vizcaino F,
pathway. Exp Biol Med. (2012) 237:822–31. doi: 10.1258/ebm.2012.012027 Zarzuelo A, et al. Antihypertensive effects of the flavonoid quercetin
106. Liang Q, Chen Y, Li C, Lu L. [Quercetin attenuates Ox-LDL-induced in spontaneously hypertensive rats. Br J Pharmacol. (2001) 133:117–
calcification in vascular smooth muscle cells by regulating ROS-TLR4 24. doi: 10.1038/sj.bjp.0704064
signaling pathway]. Nan Fang Yi Ke Da Xue Xue Bao. (2018) 38:980– 123. Galisteo M, Garcia-Saura MF, Jimenez R, Villar IC, Wangensteen R,
5. doi: 10.3969/j.issn.1673-4254.2018.08.13 Zarzuelo A, et al. Effects of quercetin treatment on vascular function in
107. Janisch KM, Williamson G, Needs P, Plumb GW. Properties of quercetin deoxycorticosterone acetate-salt hypertensive rats. Comparative study with
conjugates: modulation of LDL oxidation and binding to human serum verapamil. Planta Med. (2004) 70:334–41. doi: 10.1055/s-2004-818945
albumin. Free Radic Res. (2004) 38:877–84. doi: 10.1080/1071576041000172 124. Galisteo M, Garcia-Saura MF, Jimenez R, Villar IC, Zarzuelo A, Vargas F, et
8415 al. Effects of chronic quercetin treatment on antioxidant defence system and
108. Gong M, Garige M, Varatharajalu R, Marmillot P, Gottipatti C, Leckey LC, et oxidative status of deoxycorticosterone acetate-salt-hypertensive rats. Mol
al. Quercetin up-regulates paraoxonase 1 gene expression with concomitant Cell Biochem. (2004) 259:91–9. doi: 10.1023/b:mcbi.0000021360.89867.64
protection against LDL oxidation. Biochem Biophys Res Commun. (2009) 125. Sanchez M, Galisteo M, Vera R, Villar IC, Zarzuelo A, Tamargo J, et al.
379:1001–4. doi: 10.1016/j.bbrc.2009.01.015 Quercetin downregulates NADPH oxidase, increases eNOS activity and
109. Kondo M, Izawa-Ishizawa Y, Goda M, Hosooka M, Kagimoto Y, prevents endothelial dysfunction in spontaneously hypertensive rats. J
Saito N, et al. Preventive effects of quercetin against the onset of Hypertens. (2006) 24:75–84. doi: 10.1097/01.hjh.0000198029.22472.d9

126. Kukongviriyapan U, Sompamit K, Pannangpetch P, Kukongviriyapan 143. Jin HB, Yang YB, Song YL, Zhang YC, Li YR. Protective roles of quercetin
V, Donpunha W. Preventive and therapeutic effects of quercetin on in acute myocardial ischemia and reperfusion injury in rats. Mol Biol Rep.
lipopolysaccharide-induced oxidative stress and vascular dysfunction in (2012) 39:11005–9. doi: 10.1007/s11033-012-2002-4
mice. Can J Physiol Pharmacol. (2012) 90:1345–53. doi: 10.1139/y2012-101 144. Liu H, Guo X, Chu Y, Lu S. Heart protective effects and mechanism of
127. Shen Y, Croft KD, Hodgson JM, Kyle R, Lee IL, Wang Y, et al. Quercetin quercetin preconditioning on anti-myocardial ischemia reperfusion (IR)
and its metabolites improve vessel function by inducing eNOS activity injuries in rats. Gene. (2014) 545:149–55. doi: 10.1016/j.gene.2014.04.043
via phosphorylation of AMPK. Biochem Pharmacol. (2012) 84:1036– 145. Bartekova M, Carnicka S, Pancza D, Ondrejcakova M, Breier A, Ravingerova
44. doi: 10.1016/j.bcp.2012.07.016 T. Acute treatment with polyphenol quercetin improves postischemic
128. Li PG, Sun L, Han X, Ling S, Gan WT, Xu JW. Quercetin recovery of isolated perfused rat hearts after global ischemia. Can J Physiol
induces rapid eNOS phosphorylation and vasodilation by an Akt- Pharmacol. (2010) 88:465–71. doi: 10.1139/y10-025
independent and PKA-dependent mechanism. Pharmacology. (2012) 146. Ferenczyova K, Kalocayova B, Kindernay L, Jelemensky M, Balis P,
89:220–8. doi: 10.1159/000337182 Berenyiova A, et al. Quercetin exerts age-dependent beneficial effects on
129. Khoo NK, White CR, Pozzo-Miller L, Zhou F, Constance C, Inoue T, et al. blood pressure and vascular function, but is inefficient in preventing
Dietary flavonoid quercetin stimulates vasorelaxation in aortic vessels. Free myocardial ischemia-reperfusion injury in zucker diabetic fatty rats.
Radic Biol Med. (2010) 49:339–47. doi: 10.1016/j.freeradbiomed.2010.04.022 Molecules. (2020) 25:187. doi: 10.3390/molecules25010187
130. Romero M, Jimenez R, Sanchez M, Lopez-Sepulveda R, Zarzuelo MJ, 147. Shu Z, Yang Y, Yang L, Jiang H, Yu X, Wang Y. Cardioprotective effects of
O’Valle F, et al. Quercetin inhibits vascular superoxide production induced dihydroquercetin against ischemia reperfusion injury by inhibiting oxidative
by endothelin-1: role of NADPH oxidase, uncoupled eNOS and PKC. stress and endoplasmic reticulum stress-induced apoptosis via the PI3K/Akt
Atherosclerosis. (2009) 202:58–67. doi: 10.1016/j.atherosclerosis.2008.03.007 pathway. Food Funct. (2019) 10:203–15. doi: 10.1039/c8fo01256c
131. Qian Y, Babu PVA, Symons JD, Jalili T. Metabolites of flavonoid 148. Liu X, Yu Z, Huang X, Gao Y, Wang X, Gu J, et al. Peroxisome proliferator-
compounds preserve indices of endothelial cell nitric oxide activated receptor gamma (PPARgamma) mediates the protective effect of
bioavailability under glucotoxic conditions. Nutr Diabetes. (2017) quercetin against myocardial ischemia-reperfusion injury via suppressing
7:e286. doi: 10.1038/nutd.2017.34 the NF-kappaB pathway. Am J Transl Res. (2016) 8:5169–86.
132. Hou X, Liu Y, Niu L, Cui L, Zhang M. Enhancement of voltage-gated K+ 149. Liang Y, Zhang Y, Liu M, Han X, Zhang J, Zhang X, et al.
channels and depression of voltage-gated Ca2+ channels are involved in Protective effect of quercetin against myocardial ischemia as a
quercetin-induced vasorelaxation in rat coronary artery. Planta Med. (2014) Ca(2+) channel inhibitor: involvement of inhibiting contractility and
80:465–72. doi: 10.1055/s-0034-1368320 Ca(2+) influx via L-type Ca(2+) channels. Arch Pharm Res. (2020)
133. Hackl LP, Cuttle G, Dovichi SS, Lima-Landman MT, Nicolau M. 43:808–20. doi: 10.1007/s12272-020-01261-y
Inhibition of angiotesin-converting enzyme by quercetin alters the vascular 150. Annapurna A, Reddy CS, Akondi RB, Rao SR. Cardioprotective actions
response to brandykinin and angiotensin I. Pharmacology. (2002) 65:182– of two bioflavonoids, quercetin and rutin, in experimental myocardial
6. doi: 10.1159/000064341 infarction in both normal and streptozotocin-induced type I diabetic rats.
134. Lodi F, Winterbone MS, Tribolo S, Needs PW, Hughes DA, Kroon PA. J Pharm Pharmacol. (2009) 61:1365–74. doi: 10.1211/jpp/61.10.0014
Human quercetin conjugated metabolites attenuate TNF-alpha-induced 151. Dong LY, Chen F, Xu M, Yao LP, Zhang YJ, Zhuang Y. Quercetin attenuates
changes in vasomodulatory molecules in an HUASMCs/HUVECs co-culture myocardial ischemia-reperfusion injury via downregulation of the HMGB1-
model. Planta Med. (2012) 78:1571–3. doi: 10.1055/s-0032-1315148 TLR4-NF-kappaB signaling pathway. Am J Transl Res. (2018) 10:1273–83.
135. Zhao X, Gu Z, Attele AS, Yuan CS. Effects of quercetin on the 152. Kumar M, Kasala ER, Bodduluru LN, Kumar V, Lahkar M. Molecular and
release of endothelin, prostacyclin and tissue plasminogen activator from biochemical evidence on the protective effects of quercetin in isoproterenol-
human endothelial cells in culture. J Ethnopharmacol. (1999) 67:279– induced acute myocardial injury in rats. J Biochem Mol Toxicol. (2017)
85. doi: 10.1016/s0378-8741(99)00055-0 31:1–8. doi: 10.1002/jbt.21832
136. Loke WM, Hodgson JM, Proudfoot JM, McKinley AJ, Puddey IB, Croft KD. 153. Ma C, Jiang Y, Zhang X, Chen X, Liu Z, Tian X. Isoquercetin ameliorates
Pure dietary flavonoids quercetin and (-)-epicatechin augment nitric oxide myocardial infarction through anti-inflammation and anti-apoptosis factor
products and reduce endothelin-1 acutely in healthy men. Am J Clin Nutr. and regulating TLR4-NF-kappaB signal pathway. Mol Med Rep. (2018)
(2008) 88:1018–25. doi: 10.1093/ajcn/88.4.1018 17:6675–80. doi: 10.3892/mmr.2018.8709
137. Serban MC, Sahebkar A, Zanchetti A, Mikhailidis DP, Howard G, Antal 154. Punithavathi VR, Prince PS. Pretreatment with a combination of
D, et al. Effects of quercetin on blood pressure: a systematic review and quercetin and alpha-tocopherol ameliorates adenosine triphosphatases and
meta-analysis of randomized controlled trials. J Am Heart Assoc. (2016) lysosomal enzymes in myocardial infarcted rats. Life Sci. (2010) 86:178–
5:e002713. doi: 10.1161/JAHA.115.002713 84. doi: 10.1016/j.lfs.2009.11.021
138. Huang H, Liao D, Dong Y, Pu R. Effect of quercetin supplementation on 155. Wang Y, Zhang ZZ, Wu Y, Ke JJ, He XH, Wang YL. Quercetin
plasma lipid profiles, blood pressure, and glucose levels: a systematic review postconditioning attenuates myocardial ischemia/reperfusion injury in rats
and meta-analysis. Nutr Rev. (2020) 78:615–26. doi: 10.1093/nutrit/nuz071 through the PI3K/Akt pathway. Braz J Med Biol Res. (2013) 46:861–
139. Tamtaji OR, Milajerdi A, Dadgostar E, Kolahdooz F, Chamani M, 7. doi: 10.1590/1414-431X20133036
Amirani E, et al. The effects of quercetin supplementation on blood 156. Chekalina N, Burmak Y, Petrov Y, Borisova Z, Manusha Y, Kazakov Y, et al.
pressures and endothelial function among patients with metabolic Quercetin reduces the transcriptional activity of NF-kB in stable coronary
syndrome and related disorders: a systematic review and meta-analysis artery disease. Indian Heart J. (2018) 70:593–7. doi: 10.1016/j.ihj.2018.
of randomized controlled trials. Curr Pharm Des. (2019) 25:1372– 04.006
84. doi: 10.2174/1381612825666190513095352 157. Parkhomenko A, Kozhukhov S, Lutay Y. Multicenter randomized clinical
140. Zhu Y, Tchkonia T, Pirtskhalava T, Gower AC, Ding H, Giorgadze N, et al. trial of the efficacy and safety of intravenous quercetin in patients with ST-
The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. elevation acute myocardial infarction. Euro Heart J. (2018) 39(suppl_1):2152.
Aging Cell. (2015) 14:644–58. doi: 10.1111/acel.12344 doi: 10.1093/eurheartj/ehy565.2152
141. Jiang YH, Jiang LY, Wang YC, Ma DF, Li X. Quercetin attenuates 158. Saklayen MG. The global epidemic of the metabolic syndrome. Curr
atherosclerosis via modulating oxidized ldl-induced endothelial cellular Hypertens Rep. (2018) 20:12. doi: 10.1007/s11906-018-0812-z
senescence. Front Pharmacol. (2020) 11:512. doi: 10.3389/fphar.2020.00512 159. Guo W, Gong X, Li M. Quercetin actions on lipid profiles in overweight and
142. Hickson LJ, Langhi Prata LGP, Bobart SA, Evans TK, Giorgadze N, obese individuals: a systematic review and meta-analysis. Curr Pharm Des.
Hashmi SK, et al. Senolytics decrease senescent cells in humans: (2019) 25:3087–95. doi: 10.2174/1381612825666190829153552
preliminary report from a clinical trial of Dasatinib plus Quercetin in 160. Schoeler M, Caesar R. Dietary lipids, gut microbiota and
individuals with diabetic kidney disease. EBioMedicine. (2019) 47:446– lipid metabolism. Rev Endocr Metab Disord. (2019) 20:461–
56. doi: 10.1016/j.ebiom.2019.08.069 72. doi: 10.1007/s11154-019-09512-0

161. Ohira H, Tsutsui W, Fujioka Y. Are short chain fatty acids in gut microbiota 181. Sud N, Black SM. Endothelin-1 impairs nitric oxide signaling in endothelial
defensive players for inflammation and atherosclerosis? J Atheroscler cells through a protein kinase Cdelta-dependent activation of STAT3 and
Thromb. (2017) 24:660–72. doi: 10.5551/jat.RV17006 decreased endothelial nitric oxide synthase expression. DNA Cell Biol. (2009)
162. Istvan ES, Deisenhofer J. Structural mechanism for statin 28:543–53. doi: 10.1089/dna.2009.0865
inhibition of HMG-CoA reductase. Science. (2001) 292:1160– 182. Ohkita M, Takaoka M, Shiota Y, Nojiri R, Matsumura Y. Nitric oxide inhibits
4. doi: 10.1126/science.1059344 endothelin-1 production through the suppression of nuclear factor kappa B.
163. Faxon DP, Fuster V, Libby P, Beckman JA, Hiatt WR, Thompson Clin Sci. (2002) 103(Suppl. 48):68–71S. doi: 10.1042/CS103S068S
RW, et al. Atherosclerotic Vascular Disease Conference: Writing 183. Carretero OA. Novel mechanism of action of ACE and its
Group III: pathophysiology. Circulation. (2004) 109:2617– inhibitors. Am J Physiol Heart Circ Physiol. (2005) 289:H1796–
25. doi: 10.1161/01.CIR.0000128520.37674.EF 7. doi: 10.1152/ajpheart.00781.2005
164. Kawai Y, Nishikawa T, Shiba Y, Saito S, Murota K, Shibata N, et al. 184. Thorin E. Different contribution of endothelial nitric oxide
Macrophage as a target of quercetin glucuronides in human atherosclerotic in the relaxation of human coronary arteries of ischemic and
arteries: implication in the anti-atherosclerotic mechanism of dietary dilated cardiomyopathic hearts. J Cardiovasc Pharmacol. (2001)
flavonoids. J Biol Chem. (2008) 283:9424–34. doi: 10.1074/jbc.M706571200 37:227–32. doi: 10.1097/00005344-200102000-00010
165. Xu S, Ogura S, Chen J, Little PJ, Moss J, Liu P. LOX-1 in atherosclerosis: 185. Primikyri A, Mazzone G, Lekka C, Tzakos AG, Russo N, Gerothanassis
biological functions and pharmacological modifiers. Cell Mol Life Sci. (2013) IP. Understanding zinc(II) chelation with quercetin and luteolin: a
70:2859–72. doi: 10.1007/s00018-012-1194-z combined NMR and theoretical study. J Phys Chem B. (2015) 119:83–
166. Frostegard J, Haegerstrand A, Gidlund M, Nilsson J. Biologically modified 95. doi: 10.1021/jp509752s
LDL increases the adhesive properties of endothelial cells. Atherosclerosis. 186. Loizzo MR, Said A, Tundis R, Rashed K, Statti GA, Hufner A, et al.
(1991) 90:119–26. doi: 10.1016/0021-9150(91)90106-d Inhibition of angiotensin converting enzyme (ACE) by flavonoids isolated
167. Heinloth A, Heermeier K, Raff U, Wanner C, Galle J. Stimulation of NADPH from Ailanthus excelsa (Roxb) (Simaroubaceae). Phytother Res. (2007)
oxidase by oxidized low-density lipoprotein induces proliferation of human 21:32–6. doi: 10.1002/ptr.2008
vascular endothelial cells. J Am Soc Nephrol. (2000) 11:1819–25. Available 187. Larson AJ, Bruno RS, Guo Y, Gale D, Tanner J, Jalili T, et al.
online at: https://jasn.asnjournals.org/content/11/10/1819 Acute quercetin supplementation does not lower blood pressure
168. Katouah H, Chen A, Othman I, Gieseg SP. Oxidised low density lipoprotein or ace activity in normotensive males. J Am Diet Assoc. (2009)
causes human macrophage cell death through oxidant generation and 109:A16. doi: 10.1016/j.jada.2009.06.388
inhibition of key catabolic enzymes. Int J Biochem Cell Biol. (2015) 67:34– 188. Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van
42. doi: 10.1016/j.biocel.2015.08.001 de Sluis B, et al. Clearance of p16Ink4a-positive senescent cells delays
169. Perez-Vizcaino F, Ibarra M, Cogolludo AL, Duarte J, Zaragoza-Arnaez ageing-associated disorders. Nature. (2011) 479:232–6. doi: 10.1038/nature
F, Moreno L, et al. Endothelium-independent vasodilator effects 10600
of the flavonoid quercetin and its methylated metabolites in rat 189. Wissler Gerdes EO, Zhu Y, Tchkonia T, Kirkland JL. Discovery, development,
conductance and resistance arteries. J Pharmacol Exp Ther. (2002) and future application of senolytics: theories and predictions. FEBS J. (2020)
302:66–72. doi: 10.1124/jpet.302.1.66 287:2418–27. doi: 10.1111/febs.15264
170. Ibarra M, Perez-Vizcaino F, Cogolludo A, Duarte J, Zaragoza-Arnaez F, 190. Rodier F. Detection of the senescence-associated secretory
Lopez-Lopez JG, et al. Cardiovascular effects of isorhamnetin and quercetin phenotype (SASP). Methods Mol Biol. (2013) 965:165–
in isolated rat and porcine vascular smooth muscle and isolated rat atria. 73. doi: 10.1007/978-1-62703-239-1_10
Planta Med. (2002) 68:307–10. doi: 10.1055/s-2002-26752 191. Kampkotter A, Timpel C, Zurawski RF, Ruhl S, Chovolou Y, Proksch P,
171. Chiwororo WD, Ojewole JA. Dual effect of quercetin on rat isolated portal et al. Increase of stress resistance and lifespan of Caenorhabditis elegans
vein smooth muscle contractility. Cardiovasc J Afr. (2010) 21:132–6. by quercetin. Comp Biochem Physiol B Biochem Mol Biol. (2008) 149:314–
172. Zamponi GW, Striessnig J, Koschak A, Dolphin AC. The Physiology, 23. doi: 10.1016/j.cbpb.2007.10.004
pathology, and pharmacology of voltage-gated calcium channels 192. Olave NC, Grenett MH, Cadeiras M, Grenett HE, Higgins PJ. Upstream
and their future therapeutic potential. Pharmacol Rev. (2015) stimulatory factor-2 mediates quercetin-induced suppression of PAI-1 gene
67:821–70. doi: 10.1124/pr.114.009654 expression in human endothelial cells. J Cell Biochem. (2010) 111:720–
173. Jackson WF. KV channels and the regulation of vascular smooth muscle 6. doi: 10.1002/jcb.22760
tone. Microcirculation. (2018) 25:e12421. doi: 10.1111/micc.12421 193. Roos CM, Zhang B, Palmer AK, Ogrodnik MB, Pirtskhalava T, Thalji
174. Carvalho-de-Souza JL, Varanda WA, Tostes RC, Chignalia AZ. BK channels NM, et al. Chronic senolytic treatment alleviates established vasomotor
in cardiovascular diseases and aging. Aging Dis. (2013) 4:38–49. Available dysfunction in aged or atherosclerotic mice. Aging Cell. (2016) 15:973–
online at: http://www.aginganddisease.org/EN/Y2013/V4/I1/38 7. doi: 10.1111/acel.12458
175. Cogolludo A, Frazziano G, Briones AM, Cobeno L, Moreno L, Lodi F, et al. 194. Lamichane S, Baek SH, Kim YJ, Park JH, Dahal Lamichane B,
The dietary flavonoid quercetin activates BKCa currents in coronary arteries Jang WB, et al. MHY2233 attenuates replicative cellular senescence
via production of H2O2. Role in vasodilatation. Cardiovasc Res. (2007) in human endothelial progenitor cells via SIRT1 signaling. Oxid
73:424–31. doi: 10.1016/j.cardiores.2006.09.008 Med Cell Longev. (2019) 2019:6492029. doi: 10.1155/2019/649
176. Matoba T, Shimokawa H, Nakashima M, Hirakawa Y, Mukai Y, Hirano K, et 2029
al. Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in 195. Hwang HV, Tran DT, Rebuffatti MN, Li CS, Knowlton AA. Investigation
mice. J Clin Invest. (2000) 106:1521–30. doi: 10.1172/JCI10506 of quercetin and hyperoside as senolytics in adult human endothelial
177. Drouin A, Thorin-Trescases N, Hamel E, Falck JR, Thorin E. cells. PLoS ONE. (2018) 13:e0190374. doi: 10.1371/journal.pone.01
Endothelial nitric oxide synthase activation leads to dilatory H2O2 90374
production in mouse cerebral arteries. Cardiovasc Res. (2007) 196. Juul A, Scheike T, Davidsen M, Gyllenborg J, Jorgensen T. Low serum
73:73–81. doi: 10.1016/j.cardiores.2006.10.005 insulin-like growth factor I is associated with increased risk of ischemic
178. Drouin A, Thorin E. Flow-induced dilation is mediated by Akt- heart disease: a population-based case-control study. Circulation. (2002)
dependent activation of endothelial nitric oxide synthase-derived 106:939–44. doi: 10.1161/01.cir.0000027563.44593.cc
hydrogen peroxide in mouse cerebral arteries. Stroke. (2009) 197. Justice JN, Nambiar AM, Tchkonia T, LeBrasseur NK, Pascual R, Hashmi
40:1827–33. doi: 10.1161/STROKEAHA.108.536805 SK, et al. Senolytics in idiopathic pulmonary fibrosis: results from a
179. Thorin E, Webb DJ. Endothelium-derived endothelin-1. Pflugers Arch. first-in-human, open-label, pilot study. EBioMedicine. (2019) 40:554–
(2010) 459:951–8. doi: 10.1007/s00424-009-0763-y 63. doi: 10.1016/j.ebiom.2018.12.052
180. Cerrato R, Cunnington C, Crabtree MJ, Antoniades C, Pernow J, Channon 198. Singhal AK, Symons JD, Boudina S, Jaishy B, Shiu YT. Role of endothelial
KM, et al. Endothelin-1 increases superoxide production in human coronary cells in myocardial ischemia-reperfusion injury. Vasc Dis Prev. (2010) 7:1–
artery bypass grafts. Life Sci. (2012) 91:723–8. doi: 10.1016/j.lfs.2012.03.024 14. doi: 10.2174/1874120701007010001

199. Pagliaro BR, Cannata F, Stefanini GG, Bolognese L. Myocardial ischemia 217. Pittas K, Vrachatis DA, Angelidis C, Tsoucala S, Giannopoulos G, Deftereos
and coronary disease in heart failure. Heart Fail Rev. (2020) 25:53– S. The role of calcium handling mechanisms in reperfusion injury. Curr
65. doi: 10.1007/s10741-019-09831-z Pharm Des. (2018) 24:4077–89. doi: 10.2174/1381612825666181120155953
200. Gonzalez-Montero J, Brito R, Gajardo AI, Rodrigo R. Myocardial reperfusion 218. Guo X, Chen M, Zeng H, Liu P, Zhu X, Zhou F, et al. Quercetin
injury and oxidative stress: therapeutic opportunities. World J Cardiol. attenuates ethanol-induced iron uptake and myocardial injury by regulating
(2018) 10:74–86. doi: 10.4330/wjc.v10.i9.74 the angiotensin II-L-type calcium channel. Mol Nutr Food Res. (2018)
201. Van Hoorn DE, Nijveldt RJ, Van Leeuwen PA, Hofman Z, M’Rabet L, 62:1700772. doi: 10.1002/mnfr.201700772
De Bont DB, et al. Accurate prediction of xanthine oxidase inhibition 219. Neuhof C, Neuhof H. Calpain system and its involvement in
based on the structure of flavonoids. Eur J Pharmacol. (2002) 451:111– myocardial ischemia and reperfusion injury. World J Cardiol. (2014)
8. doi: 10.1016/s0014-2999(02)02192-1 6:638–52. doi: 10.4330/wjc.v6.i7.638
202. Lin CM, Chen CS, Chen CT, Liang YC, Lin JK. Molecular modeling of 220. Frid MG, Kale VA, Stenmark KR. Mature vascular endothelium
flavonoids that inhibits xanthine oxidase. Biochem Biophys Res Commun. can give rise to smooth muscle cells via endothelial-mesenchymal
(2002) 294:167–72. doi: 10.1016/S0006-291X(02)00442-4 transdifferentiation: in vitro analysis. Circ Res. (2002) 90:1189–
203. Mohos V, Panovics A, Fliszar-Nyul E, Schilli G, Hetenyi C, Mladenka 96. doi: 10.1161/01.res.0000021432.70309.28
P, et al. Inhibitory effects of quercetin and its human and microbial 221. Medici D, Shore EM, Lounev VY, Kaplan FS, Kalluri R, Olsen BR. Conversion
metabolites on xanthine oxidase enzyme. Int J Mol Sci. (2019) of vascular endothelial cells into multipotent stem-like cells. Nat Med. (2010)
20:2681. doi: 10.3390/ijms20112681 16:1400–6. doi: 10.1038/nm.2252
204. Huang J, Wang S, Zhu M, Chen J, Zhu X. Effects of genistein, apigenin, 222. Sanchez-Duffhues G, Orlova V, Ten Dijke P. In brief: endothelial-to-
quercetin, rutin and astilbin on serum uric acid levels and xanthine oxidase mesenchymal transition. J Pathol. (2016) 238:378–80. doi: 10.1002/path.4653
activities in normal and hyperuricemic mice. Food Chem Toxicol. (2011) 223. Moonen JR, Krenning G, Brinker MG, Koerts JA, van Luyn MJ, Harmsen
49:1943–7. doi: 10.1016/j.fct.2011.04.029 MC. Endothelial progenitor cells give rise to pro-angiogenic smooth muscle-
205. Zhu JX, Wang Y, Kong LD, Yang C, Zhang X. Effects of Biota orientalis like progeny. Cardiovasc Res. (2010) 86:506–15. doi: 10.1093/cvr/cvq012
extract and its flavonoid constituents, quercetin and rutin on serum uric 224. Potenta S, Zeisberg E, Kalluri R. The role of endothelial-to-
acid levels in oxonate-induced mice and xanthine dehydrogenase and mesenchymal transition in cancer progression. Br J Cancer. (2008)
xanthine oxidase activities in mouse liver. J Ethnopharmacol. (2004) 93:133– 99:1375–9. doi: 10.1038/sj.bjc.6604662
40. doi: 10.1016/j.jep.2004.03.037 225. Armstrong EJ, Bischoff J. Heart valve development: endothelial
206. Wan LL, Xia J, Ye D, Liu J, Chen J, Wang G. Effects of quercetin cell signaling and differentiation. Circ Res. (2004) 95:459–
on gene and protein expression of NOX and NOS after myocardial 70. doi: 10.1161/01.RES.0000141146.95728.da
ischemia and reperfusion in rabbit. Cardiovasc Ther. (2009) 27:28– 226. Kovacic JC, Mercader N, Torres M, Boehm M, Fuster V. Epithelial-
33. doi: 10.1111/j.1755-5922.2009.00071.x to-mesenchymal and endothelial-to-mesenchymal transition:
207. Guo M, Perez C, Wei Y, Rapoza E, Su G, Bou-Abdallah F, et al. Iron- from cardiovascular development to disease. Circulation. (2012)
binding properties of plant phenolics and Cranberry’s bio-effects. Dalton 125:1795–808. doi: 10.1161/CIRCULATIONAHA.111.040352
Trans. (2007) 43:4951–61. doi: 10.1039/b705136k 227. Ranchoux B, Antigny F, Rucker-Martin C, Hautefort A, Pechoux
208. Dabbagh-Bazarbachi H, Clergeaud G, Quesada IM, Ortiz M, O’Sullivan C, Bogaard HJ, et al. Endothelial-to-mesenchymal transition
CK, Fernandez-Larrea JB. Zinc ionophore activity of quercetin and in pulmonary hypertension. Circulation. (2015) 131:1006–
epigallocatechin-gallate: from Hepa 1-6 cells to a liposome model. J Agric 18. doi: 10.1161/CIRCULATIONAHA.114.008750
Food Chem. (2014) 62:8085–93. doi: 10.1021/jf5014633 228. Good RB, Gilbane AJ, Trinder SL, Denton CP, Coghlan G, Abraham DJ,
209. Bao B, Prasad AS, Beck FW, Fitzgerald JT, Snell D, Bao GW, et al. Zinc et al. Endothelial to mesenchymal transition contributes to endothelial
decreases C-reactive protein, lipid peroxidation, and inflammatory cytokines dysfunction in pulmonary arterial hypertension. Am J Pathol. (2015)
in elderly subjects: a potential implication of zinc as an atheroprotective 185:1850–8. doi: 10.1016/j.ajpath.2015.03.019
agent. Am J Clin Nutr. (2010) 91:1634–41. doi: 10.3945/ajcn.2009. 229. Piera-Velazquez S, Mendoza FA, Jimenez SA. Endothelial to mesenchymal
28836 transition (endomt) in the pathogenesis of human fibrotic diseases. J Clin
210. Yin H, Xu L, Porter NA. Free radical lipid peroxidation: mechanisms and Med. (2016) 5:45. doi: 10.3390/jcm5040045
analysis. Chem Rev. (2011) 111:5944–72. doi: 10.1021/cr200084z 230. Kriz W, Kaissling B, Le Hir M. Epithelial-mesenchymal transition (EMT)
211. Dugas AJ, Jr., Castaneda-Acosta J, Bonin GC, Price KL, Fischer NH, in kidney fibrosis: fact or fantasy? J Clin Invest. (2011) 121:468–
et al. Evaluation of the total peroxyl radical-scavenging capacity of 74. doi: 10.1172/jci44595
flavonoids: structure-activity relationships. J Nat Prod. (2000) 63:327– 231. Ma J, Sanchez-Duffhues G, Goumans MJ, Ten Dijke P. TGF-beta-induced
31. doi: 10.1021/np990352n endothelial to mesenchymal transition in disease and tissue engineering.
212. Kumar P, Sharma S, Khanna M, Raj HG. Effect of Quercetin Front Cell Dev Biol. (2020) 8:260. doi: 10.3389/fcell.2020.00260
on lipid peroxidation and changes in lung morphology in 232. van Meeteren LA, ten Dijke P. Regulation of endothelial
experimental influenza virus infection. Int J Exp Pathol. (2003) cell plasticity by TGF-beta. Cell Tissue Res. (2012) 347:177–
84:127–33. doi: 10.1046/j.1365-2613.2003.00344.x 86. doi: 10.1007/s00441-011-1222-6
213. Tang L, Peng Y, Xu T, Yi X, Liu Y, Luo Y, et al. The effects of quercetin protect 233. Medici D, Potenta S, Kalluri R. Transforming growth factor-beta2 promotes
cardiomyocytes from A/R injury is related to its capability to increasing Snail-mediated endothelial-mesenchymal transition through convergence
expression and activity of PKCepsilon protein. Mol Cell Biochem. (2013) of Smad-dependent and Smad-independent signalling. Biochem J. (2011)
382:145–52. doi: 10.1007/s11010-013-1729-0 437:515–20. doi: 10.1042/BJ20101500
214. Li B, Yang M, Liu JW, Yin GT. Protective mechanism of quercetin 234. Widyantoro B, Emoto N, Nakayama K, Anggrahini DW,
on acute myocardial infarction in rats. Genet Mol Res. (2016) Adiarto S, Iwasa N, et al. Endothelial cell-derived endothelin-1
15:15017117. doi: 10.4238/gmr.15017117 promotes cardiac fibrosis in diabetic hearts through stimulation
215. Andrassy M, Volz HC, Igwe JC, Funke B, Eichberger SN, of endothelial-to-mesenchymal transition. Circulation. (2010)
Kaya Z, et al. High-mobility group box-1 in ischemia- 121:2407–18. doi: 10.1161/CIRCULATIONAHA.110.938217
reperfusion injury of the heart. Circulation. (2008) 117:3216– 235. Wermuth PJ, Li Z, Mendoza FA, Jimenez SA. Stimulation of transforming
26. doi: 10.1161/CIRCULATIONAHA.108.769331 growth factor-beta1-induced endothelial-to-mesenchymal transition and
216. Duan SZ, Usher MG, Mortensen RM. Peroxisome proliferator- tissue fibrosis by endothelin-1 (ET-1): a novel profibrotic effect of ET-1. PLoS
activated receptor-gamma-mediated effects in the vasculature. ONE. (2016) 11:e0161988. doi: 10.1371/journal.pone.0161988
Circ Res. (2008) 102:283–94. doi: 10.1161/CIRCRESAHA.107.1 236. Li Z, Wermuth PJ, Benn BS, Lisanti MP, Jimenez SA. Caveolin-1 deficiency
64384 induces spontaneous endothelial-to-mesenchymal transition in murine

pulmonary endothelial cells in vitro. Am J Pathol. (2013) 182:325– 249. Virdis A, Masi S, Colucci R, Chiriaco M, Uliana M, Puxeddu I, et
31. doi: 10.1016/j.ajpath.2012.10.022 al. Microvascular endothelial dysfunction in patients with obesity. Curr
237. Maleszewska M, Moonen JR, Huijkman N, van de Sluis B, Krenning G, Hypertens Rep. (2019) 21:32. doi: 10.1007/s11906-019-0930-2
Harmsen MC. IL-1beta and TGFbeta2 synergistically induce endothelial 250. Engin A. Endothelial dysfunction in obesity. Adv Exp Med Biol. (2017)
to mesenchymal transition in an NFkappaB-dependent manner. 960:345–79. doi: 10.1007/978-3-319-48382-5_15
Immunobiology. (2013) 218:443–54. doi: 10.1016/j.imbio.2012.05.026 251. Shi Y, Vanhoutte PM. Macro- and microvascular endothelial dysfunction
238. Souilhol C, Harmsen MC, Evans PC, Krenning G. Endothelial- in diabetes. J Diabetes. (2017) 9:434–49. doi: 10.1111/1753-0407.
mesenchymal transition in atherosclerosis. Cardiovasc Res. (2018) 12521
114:565–77. doi: 10.1093/cvr/cvx253 252. Bozkurt B, Aguilar D, Deswal A, Dunbar SB, Francis GS, Horwich
239. Cho JG, Lee A, Chang W, Lee MS, Kim J. Endothelial to mesenchymal T, et al. Contributory risk and management of comorbidities
transition represents a key link in the interaction between of hypertension, obesity, diabetes mellitus, hyperlipidemia, and
inflammation and endothelial dysfunction. Front Immunol. (2018) metabolic syndrome in chronic heart failure: a scientific statement
9:294. doi: 10.3389/fimmu.2018.00294 from the American Heart Association. Circulation. (2016)
240. Fleenor BS, Marshall KD, Rippe C, Seals DR. Replicative aging 134:e535–78. doi: 10.1161/CIR.0000000000000450
induces endothelial to mesenchymal transition in human aortic 253. Green V. The domino effect: obesity, type 2 diabetes and
endothelial cells: potential role of inflammation. J Vasc Res. (2012) cardiovascular disease. Br J Community Nurs. (2005) 10:358–
49:59–64. doi: 10.1159/000329681 61. doi: 10.12968/bjcn.2005.10.8.18573
241. Lee ES. Biomechanical regulation of endothelial phenotype [Thesis fully 254. Sato S, Mukai Y. Modulation of chronic inflammation by
internal (DIV)]. University of Groningen, Groningen, Netherlands (2015). quercetin: the beneficial effects on obesity. J Inflamm Res. (2020)
242. Huang S, Zhu X, Huang W, He Y, Pang L, Lan X, et al. Quercetin 13:421–31. doi: 10.2147/JIR.S228361
inhibits pulmonary arterial endothelial cell transdifferentiation 255. Williamson G, Sheedy K. Effects of polyphenols on insulin resistance.
possibly by Akt and Erk1/2 pathways. Biomed Res Int. (2017) Nutrients. (2020) 12:3135. doi: 10.3390/nu12103135
2017:6147294. doi: 10.1155/2017/6147294 256. Eid HM, Haddad PS. The antidiabetic potential of quercetin:
243. Cai W, Yu D, Fan J, Liang X, Jin H, Liu C, et al. Quercetin underlying mechanisms. Curr Med Chem. (2017) 24:355–
inhibits transforming growth factor beta1-induced epithelial-mesenchymal 64. doi: 10.2174/0929867323666160909153707
transition in human retinal pigment epithelial cells via the Smad pathway. 257. Chen S, Jiang H, Wu X, Fang J. Therapeutic effects of
Drug Des Devel Ther. (2018) 12:4149–61. doi: 10.2147/DDDT.S185618 quercetin on inflammation, obesity, and type 2 diabetes.
244. Balakrishnan S, Bhat FA, Raja Singh P, Mukherjee S, Elumalai Mediators Inflamm. (2016) 2016:9340637. doi: 10.1155/2016/93
P, Das S, et al. Gold nanoparticle-conjugated quercetin inhibits 40637
epithelial-mesenchymal transition, angiogenesis and invasiveness via 258. Amiot MJ, Riva C, Vinet A. Effects of dietary polyphenols on metabolic
EGFR/VEGFR-2-mediated pathway in breast cancer. Cell Prolif. (2016) syndrome features in humans: a systematic review. Obes Rev. (2016) 17:573–
49:678–97. doi: 10.1111/cpr.12296 86. doi: 10.1111/obr.12409
245. Lu X, Chen D, Yang F, Xing N. Quercetin inhibits epithelial-to-mesenchymal
transition (emt) process and promotes apoptosis in prostate cancer via Conflict of Interest: The authors declare that the research was conducted in the
downregulating lncRNA MALAT1. Cancer Manag Res. (2020) 12:1741– absence of any commercial or financial relationships that could be construed as a
50. doi: 10.2147/CMAR.S241093 potential conflict of interest.
246. Saito A. EMT and EndMT: regulated in similar ways? J Biochem. (2013)
153:493–5. doi: 10.1093/jb/mvt032 Copyright © 2021 Dagher, Mury, Thorin-Trescases, Noly, Thorin and Carrier. This
247. McVeigh GE, Cohn JN. Endothelial dysfunction and the metabolic is an open-access article distributed under the terms of the Creative Commons
syndrome. Curr Diab Rep. (2003) 3:87–92. doi: 10.1007/s11892-003-0059-0 Attribution License (CC BY). The use, distribution or reproduction in other forums
248. Tziomalos K, Athyros VG, Karagiannis A, Mikhailidis DP. is permitted, provided the original author(s) and the copyright owner(s) are credited
Endothelial dysfunction in metabolic syndrome: prevalence, and that the original publication in this journal is cited, in accordance with accepted
pathogenesis and management. Nutr Metab Cardiovasc Dis. (2010) academic practice. No use, distribution or reproduction is permitted which does not
20:140–6. doi: 10.1016/j.numecd.2009.08.006 comply with these terms.

Dagher, Therapeutic Potential of Quercetin To Alleviate Endothelial Dysfunction in Age-Related Cardiovascular Diseases O

Uploaded by

Copyright:

Available Formats

Dagher, Therapeutic Potential of Quercetin To Alleviate Endothelial Dysfunction in Age-Related Cardiovascular Diseases O

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Dagher, Therapeutic Potential of Quercetin To Alleviate Endothelial Dysfunction in Age-Related Cardiovascular Diseases O

Uploaded by

Copyright:

Available Formats

REVIEW

published: 30 March 2021

Therapeutic Potential of Quercetin to

The vascular endothelium occupies a catalog of functions that contribute to the

Frontiers in Cardiovascular Medicine | www.frontiersin.org 1 March 2021 | Volume 8 | Article 658400

INTRODUCTION additional, yet poorly explored, therapeutic avenue. Finally, we

Frontiers in Cardiovascular Medicine | www.frontiersin.org 2 March 2021 | Volume 8 | Article 658400

Frontiers in Cardiovascular Medicine | www.frontiersin.org 3 March 2021 | Volume 8 | Article 658400

Frontiers in Cardiovascular Medicine | www.frontiersin.org 4 March 2021 | Volume 8 | Article 658400

Frontiers in Cardiovascular Medicine | www.frontiersin.org 5 March 2021 | Volume 8 | Article 658400

Frontiers in Cardiovascular Medicine | www.frontiersin.org 6 March 2021 | Volume 8 | Article 658400

Frontiers in Cardiovascular Medicine | www.frontiersin.org 7 March 2021 | Volume 8 | Article 658400

Effects Subjects Evidence and possible mechanisms References

Anti- Animals Reduced atherosclerotic plaque areas (76–84)

Frontiers in Cardiovascular Medicine | www.frontiersin.org 8 March 2021 | Volume 8 | Article 658400

Effects Subjects Evidence and possible mechanisms References

Inhibited HMGB1 and TLR4 in cardiomyocytes (151, 153)

Frontiers in Cardiovascular Medicine | www.frontiersin.org 9 March 2021 | Volume 8 | Article 658400

Frontiers in Cardiovascular Medicine | www.frontiersin.org 10 March 2021 | Volume 8 | Article 658400

Frontiers in Cardiovascular Medicine | www.frontiersin.org 11 March 2021 | Volume 8 | Article 658400

Frontiers in Cardiovascular Medicine | www.frontiersin.org 12 March 2021 | Volume 8 | Article 658400

Frontiers in Cardiovascular Medicine | www.frontiersin.org 13 March 2021 | Volume 8 | Article 658400

Frontiers in Cardiovascular Medicine | www.frontiersin.org 14 March 2021 | Volume 8 | Article 658400

Frontiers in Cardiovascular Medicine | www.frontiersin.org 15 March 2021 | Volume 8 | Article 658400

Frontiers in Cardiovascular Medicine | www.frontiersin.org 16 March 2021 | Volume 8 | Article 658400

REFERENCES 7. Zuchi C, Ambrosio G, Luscher TF, Landmesser U. Nutraceuticals in

Frontiers in Cardiovascular Medicine | www.frontiersin.org 17 March 2021 | Volume 8 | Article 658400

Frontiers in Cardiovascular Medicine | www.frontiersin.org 18 March 2021 | Volume 8 | Article 658400

Frontiers in Cardiovascular Medicine | www.frontiersin.org 19 March 2021 | Volume 8 | Article 658400

Frontiers in Cardiovascular Medicine | www.frontiersin.org 20 March 2021 | Volume 8 | Article 658400

Frontiers in Cardiovascular Medicine | www.frontiersin.org 21 March 2021 | Volume 8 | Article 658400

Frontiers in Cardiovascular Medicine | www.frontiersin.org 22 March 2021 | Volume 8 | Article 658400

Frontiers in Cardiovascular Medicine | www.frontiersin.org 23 March 2021 | Volume 8 | Article 658400

Frontiers in Cardiovascular Medicine | www.frontiersin.org 24 March 2021 | Volume 8 | Article 658400

You might also like