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Background The overall goal of this longitudinal study was to determine if the Black population has decreased myocardial function, which has the potential to lead to the early development of congestive heart failure, compared with the... more
Background The overall goal of this longitudinal study was to determine if the Black population has decreased myocardial function, which has the potential to lead to the early development of congestive heart failure, compared with the White population. Methods and Results A total of 673 subjects were evaluated over a period of 30 years including similar percentages of Black and White participants. Left ventricular systolic function was probed using the midwall fractional shortening (MFS). A longitudinal analysis of the MFS using a mixed effect growth curve model was performed. Black participants had greater body mass index, higher blood pressure readings, and greater left ventricular mass compared with White participants (all P <0.01). Black participants had a 0.54% decrease of MFS compared with White participants. As age increased by 1 year, MFS increased by 0.05%. As left ventricular mass increased by 1 g, MFS decreased by 0.01%. As circumferential end systolic stress increased...
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<jats:p> Increased body weight and elevated blood pressure could lead to the development of hyperdynamic circulation requiring increased coronary blood flow. Thus, we aimed to characterize the effects of simultaneous presence of... more
<jats:p> Increased body weight and elevated blood pressure could lead to the development of hyperdynamic circulation requiring increased coronary blood flow. Thus, we aimed to characterize the effects of simultaneous presence of obesity and hypertension on the dilator function of human coronary arterioles. Agonist-induced dilations were assessed in pressurized coronary arterioles isolated from the right atrial appendages of patients (N=38), that underwent cardiac surgery. There were no significant differences in bradykinin (BK)-induced and the nitric oxide (NO)-donor, sodium-nitroprusside (SNP)-evoked dilations of coronary arterioles between normotensive and hypertensive lean patients. In contrast, in the obese, normotensive patients BK- and SNP-induced dilations were reduced (BK, 10 <jats:sup>−7</jats:sup> M, lean:90±4%, obese:64±7%; SNP, 10 <jats:sup>−6</jats:sup> M, lean:89±7%, obese:76±5%), whereas in the obese, hypertensive patients BK- and SNP-induced dilations were significantly enhanced, when compared to lean subjects (BK, 10 <jats:sup>−7</jats:sup> M, lean:71±7%, obese:85±3%; SNP, 10 <jats:sup>−6</jats:sup> M, lean:60±6%, obese:83±2%). Correspondingly, in hypertensive individuals, but not in those of normotensives, a positive correlation was found between body mass index (BMI) and bradykinin-induced ( <jats:italic>P</jats:italic> =0.03, r=0.46), and also SNP-evoked ( <jats:italic>P&lt;</jats:italic> 0.03, r=0.44) coronary dilations. To correlate coronary responses to those of peripheral vessels, in an additional 55 hypertensive patients flow-mediated (FMD) and nitroglycerin (NTG)-induced dilations were assessed by high-resolution ultrasound. In obese, hypertensive individuals both FMD and NTG-induced dilations were significantly greater (FMD:6.2±0.7%, NTG:17.2±0.9%), than in lean hypertensive patients (FMD:3.7±0.6%, NTG:13.6±1.1%). Correspondingly, both FMD and NTG-induced dilations were positively correlated with BMI, ( <jats:italic>P</jats:italic> =0.02, r=0.31, <jats:italic>P</jats:italic> =0.03, r=0.29, respectively). These findings are the first to show that in humans obesity may lead to activation of an adaptive vascular mechanisms in hypertension, such as an increased sensitivity to NO, enhancing the dilator function of coronary and peripheral arterial vessels. </jats:p>
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<jats:p>Hyperglycemia is associated with serious microvascular complications in diabetes mellitus. We hypothesized that under high glucose concentrations, activation of the hexosamine pathway leads to protein... more
<jats:p>Hyperglycemia is associated with serious microvascular complications in diabetes mellitus. We hypothesized that under high glucose concentrations, activation of the hexosamine pathway leads to protein O-linked-N-acetylglucosamine (O-GlcNAc) formation which interferes with nitric oxide (NO)-dependent arteriolar dilation. Thus, diameter changes of skeletal muscle arterioles (diameter: ~ 160 μm) isolated from healthy, male Wistar rats were investigated after exposure to normal glucose (NG, 5.5 mM) or high glucose (HG, 30 mM for 2 hours) concentrations. In arterioles exposed to HG concentration, dilations to histamine were markedly reduced compared to those of under NG condition (max: −6±6% and 69±9%, respectively). Inhibition of NO synthesis with L-NAME reduced histamine-induced dilations in NG arterioles, but it had no effect on microvessels exposed to HG. Dilations to the NO donor, sodium nitroprusside were similar in the two groups of vessels. In the presence of the inhibitor of hexosamine pathway, azaserine histamine-induced dilations were significantly augmented and diminished by additional administration of L-NAME in arterioles exposed to HG concentrations (max: 67±2%). Moreover, under NG condition, exposure of vessels to glucosamine (5 mM, for 2 hours) resulted in reduced histamine-induced arteriolar dilations (max: 26±3%). Upon HG and glucosamine treatment an enhanced O-GlcNAc formation of endothelial NO synthase (eNOS) was detected by Western blots and immunoprecipitation. These findings indicate that high glucose concentration may lead to O-GlcNAc formation of eNOS, which impairs histamine-induced, NO-mediated arteriolar dilations. We propose that interfering with the hexosamine pathway may prevent microvascular complications in diabetes mellitus. On the other hand, our data suggest caveat for glucosamine supplementation to treat osteoarthritis, since it may impair microvascular function.</jats:p>
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In type 2 diabetes (T2D) microvascular dysfunction can interfere with tissue glucose uptake thereby contributing to the development of hyperglycemia. The cell membrane caveolae orchestrate signaling pathways that include microvascular... more
In type 2 diabetes (T2D) microvascular dysfunction can interfere with tissue glucose uptake thereby contributing to the development of hyperglycemia. The cell membrane caveolae orchestrate signaling pathways that include microvascular control of tissue perfusion. In this study, we examined the role of caveolae in the regulation of microvascular vasomotor function under the condition of hyperglycemia in T2D patients and rodent models. Human coronary arterioles were obtained during cardiac surgery from T2D patients, with higher perioperative glucose levels, and from normoglycemic, non-diabetic controls. The coronary arteriole responses to pharmacological agonists bradykinin and acetylcholine were similar in T2D and non-diabetic patients, however, exposure of the isolated arteries to methyl-β-cyclodextrin (mβCD), an agent known to disrupt caveolae, reduced vasodilation to bradykinin selectively in T2D subjects and converted acetylcholine-induced vasoconstriction to dilation similarly i...
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Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Arteriosclerosis, Thrombosis, and Vascular Biology can be obtained via RightsLink, a service of the Copyright Clearance... more
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Arteriosclerosis, Thrombosis, and Vascular Biology can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at:
Selective up-regulation of arginase-1 in coronary arteries
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Biphasic effect of hydrogen peroxide on skeletal muscle arteriolar tone via
Peroxynitrite (ONOO-) contributes to coronary microvascular dysfunction in diabetes mellitus (DM). We hypothesized that in DM ONOO- interferes with the function of coronary endothelial caveolae, which plays an important role in... more
Peroxynitrite (ONOO-) contributes to coronary microvascular dysfunction in diabetes mellitus (DM). We hypothesized that in DM ONOO- interferes with the function of coronary endothelial caveolae, which plays an important role in nitric-oxide (NO)-dependent vasomotor regulation. Flow-mediated dilation (FMD) of coronary arterioles was investigated in DM (n=41) and nonDM (n=37) patients undergoing heart surgery. NO-mediated coronary FMD was significantly reduced in DM patients, which was restored by ONOO- scavenger, iron-(III)-tetrakis(N-methyl-4'pyridyl)porphyrin-pentachloride or uric-acid, whereas exogenous ONOO- reduced FMD in nonDM subjects. Immuno-electronmicroscopy demonstrated an increased 3-nitrotyrosine formation (ONOO- specific protein nitration) in endothelial plasma membrane in DM, which co-localized with caveolin-1 (Cav-1), the key structural protein of caveolae. The membrane-localized Cav-1 was significantly reduced in DM and also in high glucose-exposed coronary endo...
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Rationale. Diabetic nephropathy (DN) is a major cause of end-stage renal disease. Hypercatabolic states are a common feature of chronic diseases such as diabetes mellitus (DM), and are accompanied ...
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Hyperinsulinemia is frequently associated with hypertension but their interrelationship remains unclear. During the progression of Type 2 diabetes mellitus (T2DM) insulin secretion may decline due ...
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Huang A, Yang YM, Feher A, Bagi Z, Kaley G, Sun D. Exacerbation of endothelial dysfunction during the progression of diabetes: role of oxidative stress. Am J Physiol Regul Integr Comp Physiol 302: R674 –R681, 2012. First published January... more
Huang A, Yang YM, Feher A, Bagi Z, Kaley G, Sun D. Exacerbation of endothelial dysfunction during the progression of diabetes: role of oxidative stress. Am J Physiol Regul Integr Comp Physiol 302: R674 –R681, 2012. First published January 18, 2012; doi:10.1152/ajpregu.00699.2011.—To test the deterioration of endothelial function during the progression of diabetes, shear stressinduced dilation (SSID; 10, 20, and 40 dyn/cm) was determined in isolated mesenteric arteries (80–120 m in diameter) of 6-wk (6W), 3-mo (3M), and 9-mo (9M)-old male db/db mice and their wild-type (WT) controls. Nitric oxide (NO)-mediated SSID was comparable in 6W WT and db/db mice, but the dilation was significantly reduced in 3M db/db mice and declined further in 9M db/db mice. Vascular superoxide production was progressively increased in 3M and 9M db/db mice, associated with an increased expression of NADPH oxidase. Inhibition of NADPH oxidase significantly improved NOmediated SSID in arteries of 3M, but not ...
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The level of inflammatory cytokines TNF, Monocyte Chemoattractant Protein (MCP-1) and Cytokine-Induced Neutrophil Chemoattractant (CINC-1) is elevated after ischemic stroke (IS). The vasomotor effects of TNF, MCP-1 and CINC-1 on cerebral... more
The level of inflammatory cytokines TNF, Monocyte Chemoattractant Protein (MCP-1) and Cytokine-Induced Neutrophil Chemoattractant (CINC-1) is elevated after ischemic stroke (IS). The vasomotor effects of TNF, MCP-1 and CINC-1 on cerebral arteries have not yet been fully elucidated after IS. We aimed to evaluate the direct effect of these cytokines on MCA diameter under normal conditions and also after IS. In isolated, pressurized middle cerebral arteries (MCA) of normal Wistar rats, TNF, CINC-1 (10-14 - 10-11 M) and MCP-1 (10-16 - 10-13 M) elicited vasodilation (max: 26±3%, 21±4% and 28±7%, respectively), which was enhanced after endothelial denudation. In rats with transient MCA occlusion, a well-known model of IS (90 min occlusion and 48 reperfusion) we observed a significantly reduced dilation to TNF, MCP-1 and CINC-1 in the ipsilateral MCA, whereas constriction of contralateral MCA was seen in response to TNF and CINC-1. We also found reduced dilations of both ipsilateral and contralateral MCA in resp...
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Abstract Background Little is known about the varied resting heart rate (RHR) trajectory patterns from childhood to young adulthood and their clinical significance. We aim to identify RHR trajectories from childhood to young adulthood,... more
Abstract Background Little is known about the varied resting heart rate (RHR) trajectory patterns from childhood to young adulthood and their clinical significance. We aim to identify RHR trajectories from childhood to young adulthood, and to determine their relationship with left ventricular mass (LVM) index. Methods RHR was measured up to 15 times over a 21-year period in 759 participants from childhood to young adulthood. LVM was measured using echocardiography and was normalised to body surface area to obtain LVM index in 546 participants. Results Using latent class models, three trajectory groups in RHR from childhood to young adulthood were identified, including high-decreasing group (HDG), moderate-decreasing group (MDG), and low-decreasing group (LDG). We found that trajectory of RHR was a significant predictor of LVM index with faster decrease of RHR associated with higher levels of total peripheral resistance (P for trend <0.001) and LVM index (P for trend <0.001). Compared to the LDG, individuals in the HDG showed higher LVM index (β = 6.08, p < 0.001). In addition, the interactions between race and RHR trajectories for LVM index was significant (p < 0.05). Conclusion Our findings show an association between RHR trajectories from childhood to young adulthood with cardiac mass, suggesting that monitoring RHR may help identify subpopulation at high cardiovascular risk.
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Myeloid cells, including monocytes/macrophages, primarily rely on glucose and lipid metabolism to provide the energy and metabolites needed for their functions and survival. AMP-activated protein kinase (AMPK, its gene is PRKA for human,... more
Myeloid cells, including monocytes/macrophages, primarily rely on glucose and lipid metabolism to provide the energy and metabolites needed for their functions and survival. AMP-activated protein kinase (AMPK, its gene is PRKA for human, Prka for rodent) is a key metabolic sensor that regulates many metabolic pathways. We studied recruitment and viability of Prkaa1-deficient myeloid cells in mice and the phenotype of these mice in the context of cardio-metabolic diseases. We found that the deficiency of Prkaa1 in myeloid cells downregulated genes for glucose and lipid metabolism, compromised glucose and lipid metabolism of macrophages, and suppressed their recruitment to adipose, liver and arterial vessel walls. The viability of macrophages in the above tissues/organs was also decreased. These cellular alterations resulted in decreases in body weight, insulin resistance, and lipid accumulation in liver of mice fed with a high fat diet, and reduced the size of atherosclerotic lesions...
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Aims Sodium-glucose-cotransporter-2 inhibitors showed favourable cardiovascular outcomes, but the underlying mechanisms are still elusive. This study investigated the mechanisms of empagliflozin in human and murine heart failure with... more
Aims Sodium-glucose-cotransporter-2 inhibitors showed favourable cardiovascular outcomes, but the underlying mechanisms are still elusive. This study investigated the mechanisms of empagliflozin in human and murine heart failure with preserved ejection fraction (HFpEF). Methods and results The acute mechanisms of empagliflozin were investigated in human myocardium from patients with HFpEF and murine ZDF obese rats, which were treated in vivo. As shown with immunoblots and ELISA, empagliflozin significantly suppressed increased levels of ICAM-1, VCAM-1, TNF-α, and IL-6 in human and murine HFpEF myocardium and attenuated pathological oxidative parameters (H2O2, 3-nitrotyrosine, GSH, lipid peroxide) in both cardiomyocyte cytosol and mitochondria in addition to improved endothelial vasorelaxation. In HFpEF, we found higher oxidative stress-dependent activation of eNOS leading to PKGIα oxidation. Interestingly, immunofluorescence imaging and electron microscopy revealed that oxidized PKG...
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Circulating extracellular vesicles (EVs) regulate signaling pathways via receptor-ligand interactions and content delivery, after attachment or internalization by endothelial cells. However, they originate from diverse cell populations... more
Circulating extracellular vesicles (EVs) regulate signaling pathways via receptor-ligand interactions and content delivery, after attachment or internalization by endothelial cells. However, they originate from diverse cell populations and are heterogeneous in composition. To determine the effects of specific surface molecules, the use of synthetic EV mimetics permits the study of specific EV receptor-ligand interactions. Here, we used endogenous EVs derived from the circulation of rats, as well as ligand-decorated synthetic microparticles (MPs) to examine the role of integrin αvβ3 in platelet adhesion under flow in structurally intact cerebral arteries. At an intraluminal pressure of 50 mmHg and flow rate of 10 µl/min, platelets were delivered to the artery lumen and imaged with whole-field fluorescent microscopy. Under basal conditions very few platelets bound to the endothelium. However, adhesion events were markedly increased following the introduction of arginine-glycine-aspart...
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Background: Heart failure with preserved ejection fraction (HFpEF) is often manifested as impaired cardiovascular reserve. We sought to determine if conducted vasodilation, which coordinates microvascular resistance longitudinally to... more
Background: Heart failure with preserved ejection fraction (HFpEF) is often manifested as impaired cardiovascular reserve. We sought to determine if conducted vasodilation, which coordinates microvascular resistance longitudinally to match tissue metabolic demand, becomes compromised in HFpEF. We hypothesized that the metabolic vasodilator adenosine facilitates and that inhibition of ADK (adenosine kinase) augments conducted vasodilation for a more efficient myocardial perfusion and improved left ventricle (LV) diastolic function in HFpEF. Methods and Results: We assessed conducted vasodilation in obese ZSF1 rats that develop LV diastolic dysfunction and is used to model human HFpEF. Additionally, conducted vasodilation was measured in arterioles isolated from the right atrial appendages of patients with HFpEF. We found a markedly reduced conducted vasodilation both in obese ZSF1 rats and in patients with HFpEF. Impaired conducted vasodilation was accompanied by increased vascular A...
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Copper transporter ATP7A (copper-transporting/exporting ATPase) is required for full activation of SOD3 (extracellular superoxide dismutase), which is secreted from vascular smooth muscle cells (VSMCs) and anchors to endothelial cell... more
Copper transporter ATP7A (copper-transporting/exporting ATPase) is required for full activation of SOD3 (extracellular superoxide dismutase), which is secreted from vascular smooth muscle cells (VSMCs) and anchors to endothelial cell surface to preserve endothelial function by scavenging extracellular superoxide. We reported that ATP7A protein expression and SOD3 activity are decreased in insulin-deficient type 1 diabetes mellitus vessels, thereby, inducing superoxide-mediated endothelial dysfunction, which are rescued by insulin treatment. However, it is unknown regarding the mechanism by which insulin increases ATP7A expression in VSMCs and whether ATP7A downregulation is observed in T2DM mice and human in which insulin-Akt pathway is selectively impaired. Here we show that ATP7A protein is markedly downregulated in vessels isolated from T2DM patients, as well as those from high-fat diet-induced or db/db T2DM mice. Akt2 activated by insulin promotes ATP7A stabilization via prevent...
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Microvascular brain injury (mVBI) is a common pathologic correlate of vascular contributions to cognitive impairment and dementia (VCID) that leads to white matter injury (WMI). VCID appears to arise from chronic recurrent white matter... more
Microvascular brain injury (mVBI) is a common pathologic correlate of vascular contributions to cognitive impairment and dementia (VCID) that leads to white matter injury (WMI). VCID appears to arise from chronic recurrent white matter ischemia that triggers oxidative stress and an increase in total oligodendrocyte lineage cells. We hypothesized that mVBI involves vasodilator dysfunction of white matter penetrating arterioles and aberrant oligodendrocyte progenitor cell (OPC) responses to WMI. We analyzed cases of mVBI with low Alzheimer's disease neuropathologic change in prefrontal cortex WM from rapid autopsies in a population-based cohort where VCID frequently occurs. Arteriolar vasodilator function was quantified by videomicroscopy. OPC maturation was quantified using lineage specific markers. ACh-mediated arteriolar dilation in mVBI was significantly reduced in WM penetrators relative to pial arterioles. Astrogliosis-defined WMI was positively associated with increased OPC...
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The molecular mechanisms underlying vascular inflammation and associated inflammatory vascular diseases are not well defined. Here we show that endothelial intracellular adenosine and its key regulator adenosine kinase (ADK) play... more
The molecular mechanisms underlying vascular inflammation and associated inflammatory vascular diseases are not well defined. Here we show that endothelial intracellular adenosine and its key regulator adenosine kinase (ADK) play important roles in vascular inflammation. Pro-inflammatory stimuli lead to endothelial inflammation by increasing endothelial ADK expression, reducing the level of intracellular adenosine in endothelial cells, and activating the transmethylation pathway through increasing the association of ADK with S-adenosylhomocysteine (SAH) hydrolase (SAHH). Increasing intracellular adenosine by genetic ADK knockdown or exogenous adenosine reduces activation of the transmethylation pathway and attenuates the endothelial inflammatory response. In addition, loss of endothelial ADK in mice leads to reduced atherosclerosis and affords protection against ischemia/reperfusion injury of the cerebral cortex. Taken together, these results demonstrate that intracellular adenosine...
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Research Interests: Endocrinology, Chemistry, Cardiology, Obesity, Cardiovascular, and 15 moreEnzyme Inhibitors, Oxidative Stress, Medicine, Metabolic syndrome, Internal Medicine, Blood Glucose, Insulin, Blood Pressure, Nitric oxide, Animals, Male, Fibrosis, Endothelial dysfunction, Arginine, and Cardiovascular medicine and haematology
Obesity-induced vascular dysfunction involves pathological remodeling of the visceral adipose tissue (VAT) and increased inflammation. Our previous studies showed that arginase 1 (A1) in endothelial cells (EC) is critically involved in... more
Obesity-induced vascular dysfunction involves pathological remodeling of the visceral adipose tissue (VAT) and increased inflammation. Our previous studies showed that arginase 1 (A1) in endothelial cells (EC) is critically involved in obesity-induced vascular dysfunction. We tested the hypothesis that EC A1 activity also drives obesity-related VAT remodeling and inflammation. Our studies utilized wild-type and EC-A1 knockout (KO) mice made obese by high fat/high sucrose (HFHS) diet. HFHS diet induced increases in body weight, fasting blood glucose, and VAT expansion. This was accompanied by increased arginase activity and A1 expression in vascular EC and increased expression of tumor necrosis factor α (TNFα), monocyte chemoattractant protein-1 (MCP-1), interleukin-10 (IL-10), vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) mRNA and protein in both VAT and EC. HFHS also markedly increased circulating inflammatory monocytes and VAT infiltrati...
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The nucleoside adenosine is a potent regulator of vascular homeostasis, but it remains unclear how expression or function of the adenosine-metabolizing enzyme adenosine kinase (ADK) and the intracellular adenosine levels influence... more
The nucleoside adenosine is a potent regulator of vascular homeostasis, but it remains unclear how expression or function of the adenosine-metabolizing enzyme adenosine kinase (ADK) and the intracellular adenosine levels influence angiogenesis. We show here that hypoxia lowered the expression of ADK and increased the levels of intracellular adenosine in human endothelial cells. Knockdown (KD) of ADK elevated intracellular adenosine, promoted proliferation, migration, and angiogenic sprouting in human endothelial cells. Additionally, mice deficient in endothelial ADK displayed increased angiogenesis as evidenced by the rapid development of the retinal and hindbrain vasculature, increased healing of skin wounds, and prompt recovery of arterial blood flow in the ischemic hindlimb. Mechanistically, hypomethylation of the promoters of a series of pro-angiogenic genes, especially for VEGFR2 in ADK KD cells, was demonstrated by the Infinium methylation assay. Methylation-specific PCR, bisu...
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A disintegrin and metalloproteinase ADAM17 (tumor necrosis factor-α [TNF]-converting enzyme) regulates soluble TNF levels. We tested the hypothesis that aging-induced activation in adipose tissue (AT)-expressed ADAM17 contributes to the... more
A disintegrin and metalloproteinase ADAM17 (tumor necrosis factor-α [TNF]-converting enzyme) regulates soluble TNF levels. We tested the hypothesis that aging-induced activation in adipose tissue (AT)-expressed ADAM17 contributes to the development of remote coronary microvascular dysfunction in obesity. Coronary arterioles (CAs, ≈90 µm) from right atrial appendages and mediastinal AT were examined in patients (aged: 69±11 years, BMI: 30.2±5.6) who underwent open heart surgery. CA and AT were also studied in 6-month and 24-month lean and obese mice fed a normal or high-fat diet. We found that obesity elicited impaired endothelium-dependent CA dilations only in older patients and in aged high-fat diet mice. Transplantation of AT from aged obese, but not from young or aged, mice increased serum cytokine levels, including TNF, and impaired CA dilation in the young recipient mice. In patients and mice, obesity was accompanied by age-related activation of ADAM17, which was attributed to ...
Research Interests: Endocrinology, Aging, Medicine, Adipose tissue, Humans, and 15 moreInternal Medicine, Endothelial Cells, Female, Animals, Male, Endothelial dysfunction, Clinical Sciences, Aged, Adult, Age Factors, ENDOTHELIUM, Coronary Artery Disease, Arterioles, Cardiovascular medicine and haematology, and Coronary Vessels
Impaired adipogenic differentiation during diet-induced obesity (DIO) promotes adipocyte hypertrophy and inflammation, thereby contributing to metabolic disease. Adenomatosis polyposis coli downregulated 1 (APCDD1) has recently been... more
Impaired adipogenic differentiation during diet-induced obesity (DIO) promotes adipocyte hypertrophy and inflammation, thereby contributing to metabolic disease. Adenomatosis polyposis coli downregulated 1 (APCDD1) has recently been identified as an inhibitor of Wnt signaling, a key regulator of adipogenic differentiation. Here, we report a novel role for APCDD1 in adipogenic differentiation via repression of Wnt signaling, and an epigenetic linkage between miR-130 and APCDD1 in DIO. APCDD1 expression was significantly upregulated in mature adipocytes as compared to undifferentiated preadipocytes in both human and mouse subcutaneous adipose tissues. siRNA-based silencing of APCDD1 in 3T3-L1 preadipocytes markedly increased expression of Wnt signaling proteins (Wnt3a, Wnt5a, Wnt10b, LRP5, β-catenin), and inhibited expression of adipocyte differentiation markers (C/EBPα, PPARγ and lipid droplet accumulation, while adenovirus-mediated overexpression of APCDD1 enhanced adipogenic differ...