Pulmonary hypertension (PH) is a debilitating, chronic lung disease that often leads to right-heart failure and death. Currently available therapies are ineffective in significantly improving the quality of life and reducing mortality... more
Pulmonary hypertension (PH) is a debilitating, chronic lung disease that often leads to right-heart failure and death. Currently available therapies are ineffective in significantly improving the quality of life and reducing mortality rates, thereby necessitating the discovery of novel therapeutic interventions. The renin-angiotensin system (RAS) has been associated with the pathophysiology of PH, via increased activity of the deleterious ACE/ANGII/AT1R axis. It has been suggested that AT2R are upregulated in response to cardiovascular injury, and subsequent stimulation of this receptor may oppose the deleterious actions of the RAS axis. However, the role of AT2R in PH has yet to be investigated. We propose that non-peptide AT2R agonist, Compound-21 (C21), will attenuate the progression of monocrotaline (MCT)-induced PH in 8-week-old Sprague Dawley rats. Four weeks post a subcutaneous injection of MCT (50mg/Kg), the rats displayed marked elevation in right ventricular systolic press...
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The dysfunctional nature of CD34 cells from patients with heart failure (HF) may make them unsuitable for autologous stem-cell therapy. In view of evidence that the vasoprotective axis of the renin-angiotensin system (RAS) improves CD34... more
The dysfunctional nature of CD34 cells from patients with heart failure (HF) may make them unsuitable for autologous stem-cell therapy. In view of evidence that the vasoprotective axis of the renin-angiotensin system (RAS) improves CD34 cell functions, we hypothesized that CD34 cells from patients with HF will be dysfunctional and that angiotensin-(1-7) [Ang-(1-7)] would improve their function. Peripheral blood was collected from New York Heart Association class II-IV patients with HF (n = 31) and reference subjects (n = 16). CD34 cell numbers from patients with HF were reduced by 47% (P < 0.05) and also displayed 76% reduction in migratory capacity and 56% (P < 0.05) lower production of nitric oxide. These alterations were associated with increases in RAS genes angiotensin-converting enzyme and AT2R (595%, P < 0.05) mRNA levels and 80% and 85% decreases in angiotensin-converting enzyme 2 and Mas mRNA levels, respectively. Treatment with Ang-(1-7) enhanced CD34 cell functio...
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Pulmonary hypertension (PH) and pulmonary fibrosis (PF) are life threatening cardiopulmonary diseases. Existing pharmacological interventions have failed to improve clinical outcomes or reduce disease-associated mortality. Emerging... more
Pulmonary hypertension (PH) and pulmonary fibrosis (PF) are life threatening cardiopulmonary diseases. Existing pharmacological interventions have failed to improve clinical outcomes or reduce disease-associated mortality. Emerging evidence suggests that stem cells offer an effective treatment approach against various pathological conditions. It has been proposed that their beneficial actions may be mediated via secretion of paracrine factors. Herein, we evaluated the therapeutic potential of conditioned media (CM) from Adipose Stem Cells (ASCs) against experimental models of PH and PF. Monocrotaline (MCT) or Bleomycin (Bleo) was injected into male Sprague-Dawley rats to induce PH or PF, respectively. A subset of MCT and Bleo animals were treated with ASCs or CM. Echocardiographic and hemodynamic measurements were performed at the end of the study. Lung and heart tissues were harvested for RNA, protein and histological measurements. CM treatment attenuated MCT-induced PH by improvin...
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Over-activation of brain renin-angiotensin system (RAS) has been implicated in the etiology of anxiety disorders. Angiotensin converting enzyme (ACE2) inhibits RAS activity by converting angiotensin II, the effector peptide of RAS, to... more
Over-activation of brain renin-angiotensin system (RAS) has been implicated in the etiology of anxiety disorders. Angiotensin converting enzyme (ACE2) inhibits RAS activity by converting angiotensin II, the effector peptide of RAS, to angiotensin-(1-7), which activates Mas receptors (MasR). Whether increasing brain ACE2 activity reduces anxiety by stimulating central MasR is unknown. To test the hypothesis that increasing brain ACE2 activity reduces anxiety-like behavior via central MasR stimulation, we generated male mice overexpressing ACE2 (ACE2 KI mice) and wild type littermate controls (WT). ACE2 KI mice explored the open arms of the elevated plus maze (EPM) significantly more than WT, suggesting increasing ACE2 activity is anxiolytic. Central delivery of diminazene aceturate, an ACE2 activator, to C57BL/6 mice also reduced anxiety-like behavior in the EPM, but centrally administering ACE2 KI mice A-779, a MasR antagonist, abolished their anxiolytic phenotype, suggesting that A...
Research Interests: Endocrinology, Chemistry, Neuropharmacology, Medicine, Anxiety, and 15 moreInternal Medicine, Mice, Animals, Male, GABA, Neurons, Elevated Plus Maze, ANXIETY, ACE, Angiotensin II, Neurosciences, Basolateral Amygdala, G Protein Coupled Receptors, Mas receptor, and Pharmacology and pharmaceutical sciences
The aim of the present study was to test the hypothesis that the activation of the angiotensin-converting enzyme (ACE)2/angiotensin-(1-7)/Mas receptor axis by use of a novel ACE2 activator (XNT) would protect against thrombosis. Thrombi... more
The aim of the present study was to test the hypothesis that the activation of the angiotensin-converting enzyme (ACE)2/angiotensin-(1-7)/Mas receptor axis by use of a novel ACE2 activator (XNT) would protect against thrombosis. Thrombi were induced in the vena cava of spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) rats, and ACE2 and ACE activity in the thrombus was determined. Real-time thrombus formation was viewed through intravital microscopy of vessels in nude mice. Thrombus weight was 40% greater in the SHR (4.99 +/- 0.39 versus 7.04 +/- 0.66 mg). This weight increase was associated with a 20% decrease in ACE2 activity in the thrombus. In contrast, there were no differences between the WKY and SHR in ACE2 protein and ACE activity in the thrombi. ACE2 inhibition (DX600; 0.1 micromol/L/kg) increased thrombus weight by 30% and XNT treatment (10 mg/kg) resulted in a 30% attenuation of thrombus formation in the SHR. Moreover, XNT reduced platelet attachment to injured...
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Research Interests: Endocrinology, Biology, Medicine, Echocardiography, Internal Medicine, and 15 moreHyperglycemia, Diabetes mellitus, Animals, Male, Heart, AMPK, Fibrosis, Left Ventricular Dysfunction, Rats, Cardiac Fibrosis, Angiotensin Converting Enzyme, Cardiomegaly, G Protein Coupled Receptors, diabetic cardiomyopathy, and Medical and Health Sciences
Hypertension produces pathophysiological changes that are often responsible for the mortality associated with the disease. However, it is unclear whether normalizing blood pressure (BP) with conventional therapy is effective in reversing... more
Hypertension produces pathophysiological changes that are often responsible for the mortality associated with the disease. However, it is unclear whether normalizing blood pressure (BP) with conventional therapy is effective in reversing the pathophysiological damage. The duration and initiation of treatment, site of administration, and agent used all appear to influence the reversal of the pathophysiological alterations associated with hypertension. We have previously established that retrovirally mediated delivery of angiotensin II type 1 receptor antisense (AT 1 R-AS) attenuates the development of high BP in the spontaneously hypertensive (SH) rat model of human essential hypertension. Our objective was to determine whether this attenuation of high BP is associated with prevention of other pathophysiological changes induced by the hypertensive state. Intracardiac delivery of AT 1 R-AS in neonates prevented the development of hypertension in SH rats for at least 120 days. Contract...
Research Interests: Endocrinology, Gene Therapy, Medicine, Humans, Internal Medicine, and 15 moreHypertension, Blood Pressure, Animals, Heart, Acetylcholine, Current Density, Fibrosis, Left ventricular hypertrophy, Angiotensin II, Heart Ventricles, Essential Hypertension, Cardiomegaly, Genetic Therapy, In Vitro Techniques, and Coronary Vessels
Diminished release and function of endothelium-derived nitric oxide coupled with increases in reactive oxygen species production is critical in endothelial dysfunction. Recent evidences have shown that activation of the protective axis of... more
Diminished release and function of endothelium-derived nitric oxide coupled with increases in reactive oxygen species production is critical in endothelial dysfunction. Recent evidences have shown that activation of the protective axis of the renin–angiotensin system composed by angiotensin-converting enzyme 2, angiotensin-(1–7), and Mas receptor promotes many beneficial vascular effects. This has led us to postulate that activation of intrinsic angiotensin-converting enzyme 2 would improve endothelial function by decreasing the reactive oxygen species production. In the present study, we tested 1-[[2-(dimetilamino)etil]amino]-4-(hidroximetil)-7-[[(4-metilfenil)sulfonil]oxi]-9H-xantona-9 (XNT), a small molecule angiotensin-converting enzyme 2 activator, on endothelial function to validate this hypothesis. In vivo treatment with XNT (1 mg/kg per day for 4 weeks) improved the endothelial function of spontaneously hypertensive rats and of streptozotocin-induced diabetic rats when evalu...
Research Interests: Endocrinology, Chemistry, Immunohistochemistry, Oxidative Stress, Medicine, and 15 moreHumans, Internal Medicine, Hypertension, Mice, Nitric oxide, Animals, Male, Endothelial dysfunction, Clinical Sciences, Rats, Angiotensin Converting Enzyme, ENDOTHELIUM, Angiotensin II, Radioimmunoassay, and Cardiovascular medicine and haematology
AT 1 receptor subtype a (AT 1 Ra) expression is increased in the nucleus of the solitary tract (NTS) in spontaneously hypertensive rat (SHR) compared with Wistar Kyoto controls. However, the chronic role of AT 1 Ra in the NTS for... more
AT 1 receptor subtype a (AT 1 Ra) expression is increased in the nucleus of the solitary tract (NTS) in spontaneously hypertensive rat (SHR) compared with Wistar Kyoto controls. However, the chronic role of AT 1 Ra in the NTS for cardiovascular control is not well understood. In this study, we investigated the hypothesis that the NTS AT 1 Ra is involved in the neural regulation of the peripheral inflammatory status and linked with hypertension. Transduction of brain neuronal cultures with recombinant adeno-associated virus type 2 (AAV2)-AT 1 R-small hairpin RNA (shRNA) resulted in a 72% decrease in AT 1 Ra mRNA and attenuated angiotensin II–induced increase in extracellular signal–regulated kinase 1/2 phosphorylation and neuronal firing. Specific NTS microinjection of AAV2-AT 1 R-shRNA vector in the SHR resulted in a ≈30 mm Hg increase in the mean arterial pressure compared with control vector–injected animals (Sc-shRNA: 154±4 mm Hg; AT 1 R-shRNA: 183±10 mm Hg) and induced a resetti...
Research Interests: Endocrinology, Stem Cells, Biology, Inflammation, Medicine, and 11 moreInternal Medicine, Hypertension, Endothelial Cells, Blood Pressure, Animals, Clinical Sciences, Rats, Disease Progression, Gene Expression Regulation, real time polymerase chain reaction, and Cardiovascular medicine and haematology
We have previously shown that a decrease in hypothalamic gamma adducin (γ-adducin) is associated with hypertension in the spontaneously hypertensive rat (SHR). In view of many inherent issues with SHR, our objective in the present study... more
We have previously shown that a decrease in hypothalamic gamma adducin (γ-adducin) is associated with hypertension in the spontaneously hypertensive rat (SHR). In view of many inherent issues with SHR, our objective in the present study was to provide proof of this concept with the use of 2 nongenetic rat models of hypertension. Subcutaneous angiotensin II (Ang II) infusion for 2 weeks (55 ng/kg per day) resulted in an increase in blood pressure (BP) of 18 mm Hg. This was associated with a 70% decrease in hypothalamic γ-adducin. Concomitant administration of losartan attenuated the development of hypertension and a decrease in γ-adducin. Deoxycorticosterone acetate salt-induced hypertension also caused a 70% decrease in hypothalamic γ-adducin. Finally, neuronal cultures from neonatal rat brains were incubated with 100 nmol/L Ang II for 4 hours to mimic the in vivo Ang II infusion rat model. This chronic incubation with Ang II resulted in a 60% decrease in the neuronal γ-adducin. Tak...
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Research Interests: Endocrinology, Biology, Gene Therapy, Cell line, Cardiac Hypertrophy, and 15 moreBlood Pressure, Female, Animals, Animal Model, Acetylcholine, Angiotensins, Endothelial dysfunction, Clinical Sciences, Gene Delivery, Coronary Circulation, Angiotensin Converting Enzyme, Bradykinin, Cardiomegaly, Genetic Therapy, and Cardiovascular medicine and haematology
Research Interests: Endocrinology, Calcium, Medicine, Patch-clamp and imaging techniques, Internal Medicine, and 14 moreHypertension, Blood Pressure, Animals, Male, Vasoconstriction, Clinical Sciences, Rats, Homeostasis, Angiotensin II, Potassium Chloride, Vascular Resistance, Arterioles, Genetic Therapy, and Cardiovascular medicine and haematology
Angiotensin converting enzyme 2 (ACE2) has been linked to cardiac dysfunction and hypertension-induced cardiac pathophysiology. In this study, we used a gene overexpression approach to investigate the role of ACE2 in cardiac function and... more
Angiotensin converting enzyme 2 (ACE2) has been linked to cardiac dysfunction and hypertension-induced cardiac pathophysiology. In this study, we used a gene overexpression approach to investigate the role of ACE2 in cardiac function and remodeling after myocardial infarction. Rats received an intracardiac injection of 4.5×10 8 lentivirus containing ACE2 cDNA, followed by permanent coronary artery ligation (CAL) of the left anterior descending artery. At 24 hours and 6 weeks after surgery, cardiac functions, viability, and pathophysiology were assessed by MRI) and by histological analysis. At 24 hours post-CAL, left ventricular (LV) anterior wall motion was stunted to the same extent in control CAL and lenti-ACE2–treated CAL rats. However lenti-ACE2–treated CAL rats showed a 60% reduction in delayed contrast-enhanced LV volume after gadodiamide injection, indicating early ischemic protection of myocardium by ACE2. At 6 weeks after CAL, lenti-ACE2 rats demonstrated a complete rescue ...
Research Interests: Cardiology, Magnetic Resonance Imaging, Gene Therapy, Medicine, Internal Medicine, and 15 moreHypertension, Animals, Male, Heart, Lentivirus, Heart Disease, Clinical Sciences, Myocardial Infarction, Angiotensin Converting Enzyme, Ejection Fraction, Coronary artery, Cardiac function, Contractility, Genetic Therapy, and Cardiovascular medicine and haematology
Our studies have established that a single intracardiac administration of the retroviral vector containing angiotensin II type I receptor antisense gene causes prolonged antihypertensive actions in the spontaneously hypertensive rat.... more
Our studies have established that a single intracardiac administration of the retroviral vector containing angiotensin II type I receptor antisense gene causes prolonged antihypertensive actions in the spontaneously hypertensive rat. These results suggest that antisense gene therapy is a conceptually valid strategy for the control of hypertension at the genetic level. To evaluate whether attenuation of the pathophysiological aspects of hypertension are dependent on the blood pressure lowering actions of antisense gene therapy, we chose the renin transgenic rat as a hypertensive animal model and cardiac hypertrophy as the hypertension-associated pathophysiology. A single intracardiac administration of the retroviral vector containing angiotensin II type I receptor antisense in the neonatal rat resulted in long-term expression of the antisense transgene in various cardiovascular-relevant tissues, including the heart. This expression was associated with a significant attenuation of car...
Research Interests: Genetics, Gene Therapy, Gene expression, Cardiac Hypertrophy, Internal Medicine, and 15 moreHypertension, High Blood Pressure, Genetic Enhancement, Blood Pressure, Female, Animals, Male, Animal Model, Clinical Sciences, Left ventricular hypertrophy, Angiotensin II, Atrial Natriuretic Factor, Cardiomegaly, Genetic Therapy, and Cardiovascular medicine and haematology
Research Interests: Endocrinology, Biology, Medicine, Experimental Physiology, Internal Medicine, and 15 moreHypertension, Collagen, Animals, Male, Heart, Phosphorylation, Fibrosis, Medical Physiology, Experimental, Myocardium, Cardiac Fibrosis, Angiotensin Converting Enzyme, Angiotensin II, fibroblasts, and Cell culture techniques
Rationale: Despite overwhelming evidence of the importance of brain renin–angiotensin system (RAS), the very existence of intrinsic brain RAS remains controversial. Objective: To investigate the hypothesis that the brain (pro)renin... more
Rationale: Despite overwhelming evidence of the importance of brain renin–angiotensin system (RAS), the very existence of intrinsic brain RAS remains controversial. Objective: To investigate the hypothesis that the brain (pro)renin receptor (PRR) is physiologically important in the brain RAS regulation and cardiovascular functions. Methods and Results: PRR is broadly distributed within neurons of cardiovascular-relevant brain regions. The physiological functions of PRR were studied in the supraoptic nucleus (SON) because this brain region showed greater levels of PRR mRNA in the spontaneously hypertensive rats (SHR) compared with normotensive Wistar–Kyoto (WKY) rats. Adeno-associated virus (AAV)-mediated overexpression of human PRR in the SON of normal rats resulted in increases in plasma and urine vasopressin, and decreases in H 2 O intake and urine output without any effects on mean arterial pressure and heart rate. Knockdown of endogenous PRR by AAV-short hairpin RNA in the SON o...
Research Interests: Endocrinology, Biology, Medicine, Internal Medicine, Hypertension, and 15 moreHemodynamics, Blood Pressure, Renin Angiotensin Aldosterone System, Animals, Male, Supraoptic Nucleus, Clinical Sciences, Cardiovascular system, Rats, Homeostasis, Circulation, Receptor, Arterial pressure, Cardiovascular medicine and haematology, and Renin
Research Interests: Endocrinology, Gene Therapy, Medicine, Cardiac Hypertrophy, Internal Medicine, and 15 moreHypertension, Low Dose, Blood Pressure, Female, Animals, Gene transfer techniques, Clinical Sciences, Rats, Delivery System, Circulation, Drinking, Angiotensin II, Contractility, Cardiomegaly, and Cardiovascular medicine and haematology
Research Interests: Endocrinology, Genetics, Gene Therapy, Cardiac Hypertrophy, Internal Medicine, and 15 moreKidney, Hypertension, Blood Pressure, Animals, Animal Model, Fibrosis, Clinical Sciences, Delivery System, Circulation, Losartan, Angiotensin II, Aorta, Genetic Therapy, Antihypertensive agents, and Cardiovascular medicine and haematology
Research Interests: Genetics, Biology, Medicine, Hypertension, Blood Pressure, and 15 moreAnimals, Vascular endothelium, Clinical Sciences, Rats, Endothelial cell, Circulation, Side Effect, Angiotensin Converting Enzyme, Angiotensin II, Angiotensin Converting Enzyme Inhibitors, ACE Inhibitor, Gene Transfer, Pulmonary Artery, Antihypertensive agents, and Cardiovascular medicine and haematology
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Cardiac remodeling is a hallmark hypertension-induced pathophysiology. In the current study, the role of the angiotensin-(1–7) fragment in modulating cardiac remodeling was examined. Sprague-Dawley rats underwent uninephrectomy surgery... more
Cardiac remodeling is a hallmark hypertension-induced pathophysiology. In the current study, the role of the angiotensin-(1–7) fragment in modulating cardiac remodeling was examined. Sprague-Dawley rats underwent uninephrectomy surgery and were implanted with a deoxycorticosterone acetate (DOCA) pellet. DOCA animals had their drinking water replaced with 0.9% saline solution. A subgroup of DOCA-salt animals was implanted with osmotic minipumps, which delivered angiotensin-(1–7) chronically (100 ng·kg−1·min−1). Control animals underwent sham surgery and were maintained on normal drinking water. Blood pressure was measured weekly with the use of the tail-cuff method, and after 4 wk of treatment, blood pressure responses to graded doses of angiotensin II were determined by direct carotid artery cannulation. Ventricle size was measured, and cross sections of the heart ventricles were paraffin embedded and stained using Masson's Trichrome to measure interstitial and perivascular coll...
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Research Interests: Endocrinology, Diet, Insulin Resistance, Internal Medicine, Insulin, and 15 moreHyperinsulinemia, Animals, Exploration, Fructose, Clinical Sciences, Hormone, Body Weight, Losartan, Imidazoles, Glucose Tolerance Test, Long Term, Angiotensin II, Cardiomegaly, Antihypertensive agents, and Angiotensin Receptor Antagonists
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Research Interests: Endocrinology, Electrophysiology, Gene Therapy, Calcium, Cell line, and 15 moreBlood Pressure, Female, Animals, Calcium channels, Calcium Channel, Acetylcholine, Current Density, Enzyme, Clinical Sciences, Gene Delivery, Angiotensin Converting Enzyme, Angiotensin II, ACE Inhibitor, Arterioles, and Cardiovascular medicine and haematology
Cardiac remodelling is a key risk factor for the development of heart failure in the chronic phase following myocardial infarction. Our previous studies have shown an anti-remodelling role of ACE2 (angiotensin-converting enzyme 2) in vivo... more
Cardiac remodelling is a key risk factor for the development of heart failure in the chronic phase following myocardial infarction. Our previous studies have shown an anti-remodelling role of ACE2 (angiotensin-converting enzyme 2) in vivo during hypertension and that these protective effects are mediated through increased circulating levels of Ang-(1–7) [angiotensin-(1–7)]. In the present study, we have demonstrated that cardiac myocytes have modest ACE2 activity, whereas cardiac fibroblasts do not exhibit any endogenous activity. As fibroblasts are the major cell type found in an infarct zone following a myocardial infarction, we examined the effects of ACE2 gene delivery to cultured cardiac fibroblasts after acute hypoxic exposure. Cardiac fibroblasts from 5-day-old Sprague–Dawley rat hearts were grown to confluence and transduced with a lentiviral vector containing murine ACE2 cDNA under transcriptional control by the EF1α (elongation factor 1α) promoter (lenti-ACE2). Transductio...
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Research Interests: Physiology, Medicine, Experimental Physiology, Stroke, Ischemia, and 15 moreAnimals, Male, Anesthesia, Brain Ischemia, Medical Physiology, Experimental, Rats, Occlusion, Rat Model, Benzimidazoles, Angiotensin II, Middle Cerebral Artery, Cerebral Infarction, Tetrazoles, and Middle cerebral artery occlusion
In spite of recent advancements in the treatment of pulmonary hypertension, successful control has yet to be accomplished. The abundant presence of angiotensin-converting enzyme 2 (ACE2) in the lungs and its impressive effect in the... more
In spite of recent advancements in the treatment of pulmonary hypertension, successful control has yet to be accomplished. The abundant presence of angiotensin-converting enzyme 2 (ACE2) in the lungs and its impressive effect in the prevention of acute lung injury led us to test the hypothesis that pulmonary overexpression of this enzyme could produce beneficial outcomes against pulmonary hypertension. Monocrotaline
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Pharmacological blockade of the renin-angiotensin system in both hypertensive patients and animal models such as the spontaneously hypertensive rat (SHR) effectively reduces blood pressure (BP). Recent studies have established that... more
Pharmacological blockade of the renin-angiotensin system in both hypertensive patients and animal models such as the spontaneously hypertensive rat (SHR) effectively reduces blood pressure (BP). Recent studies have established that virally mediated delivery (vector LNSV) of antisense to the angiotensin II type 1 receptor (LNSV-AT1R-AS) will attenuate or abolish the development of hypertension in the SHR. However, the effectiveness of this gene therapy approach to reduce high BP once it is established in the adult has not been ascertained. In this study, we investigated the hypothesis that viral delivery of AT1R-AS into the adult SHR will reduce BP and reverse the vascular reactivity associated with the hypertension. Intracardiac injection of virus particles containing LNSV-AT1R-AS into adult SHR resulted in a 30- to 60-mmHg reduction in BP that was maintained for up to 36 days compared with SHR treated with virus alone (LNSV without antisense). Measurement of renal resistance arteri...
Research Interests: Physiology, Microcirculation, Medicine, Hypertension, Hemodynamics, and 13 moreGenetic Enhancement, Blood Pressure, Renin Angiotensin Aldosterone System, Animals, Animal Model, Medical Physiology, Rats, Rat, Urinary System, Receptor, Gene Expression Regulation, Vascular Resistance, and Genetic Therapy
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Pulmonary hypertension (PH) is a devastating disease and its successful treatment remains to be accomplished despite recent advances in pharmacotherapy. It has been proposed that PH be considered as a systemic disease, rather than... more
Pulmonary hypertension (PH) is a devastating disease and its successful treatment remains to be accomplished despite recent advances in pharmacotherapy. It has been proposed that PH be considered as a systemic disease, rather than primarily a disease of the pulmonary vasculature. Consequently, an investigation of the intricate interplay between multiple organs such as brain, vasculature, and lung in PH could lead to the identification of new targets for its therapy. However, little is known about this interplay. This study was undertaken to examine the concept that altered autonomic-pulmonary communication is important in PH pathophysiology. Therefore, we hypothesize that activation of microglial cells in the paraventricular nucleus of hypothalamus and neuroinflammation is associated with increased sympathetic drive and pulmonary pathophysiology contributing to PH. We utilized the monocrotaline rat model for PH and intracerebroventricular administration of minocycline for inhibition...
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Idiopathic Pulmonary Fibrosis (IPF) is a chronic lung disease characterized by scar formation and respiratory insufficiency, which progressively leads to death. Pulmonary hypertension (PH) is a common complication of IPF that negatively... more
Idiopathic Pulmonary Fibrosis (IPF) is a chronic lung disease characterized by scar formation and respiratory insufficiency, which progressively leads to death. Pulmonary hypertension (PH) is a common complication of IPF that negatively impacts clinical outcomes, and has been classified as Group III PH. Despite scientific advances, the dismal prognosis of IPF and associated PH remains unchanged, necessitating the search for novel therapeutic strategies. Accumulating evidence suggests that stimulation of the angiotensin II type 2 (AT) receptor confers protection against a host of diseases. In this study, we investigated the therapeutic potential of Compound 21 (C21), a selective AT receptor agonist in the bleomycin model of lung injury. A single intra-tracheal administration of bleomycin (2.5 mg/kg) to 8-week old male Sprague Dawley rats resulted in lung fibrosis and PH. Two experimental protocols were followed: C21 was administered (0.03 mg/kg/day, ip) either immediately (prevention...
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This article is based on an Experimental Biology symposium held in April 2001 and presents the current status of gene therapy for cardiovascular diseases in experimental studies and clinical trials. Evidence for the use of gene therapy to... more
This article is based on an Experimental Biology symposium held in April 2001 and presents the current status of gene therapy for cardiovascular diseases in experimental studies and clinical trials. Evidence for the use of gene therapy to limit neointimal hyperplasia and confer myocardial protection was presented, and it was found that augmenting local nitric oxide (NO) production using gene transfer (GT) of NO synthase or interruption of cell cycle progression through a genetic transfer of cell cycle regulatory genes limited vascular smooth muscle hyperplasia in animal models and infra-inguinal bypass patients. The results of application of vascular endothelial growth factor (VEGF) GT strategies for therapeutic angiogenesis in critical limb and myocardial ischemia in pilot clinical trials was reviewed. In addition, experimental evidence was presented that genetic manipulation of peptide systems (i.e., the renin-angiotensin II system and the kallikrein-kinin system) was effective in...
Research Interests: Bioinformatics, Genetics, Clinical Trial, Biology, Treatment Outcome, and 15 moreMedicine, Angiogenesis, Humans, Genetic Enhancement, Animals, Physiological, Medical Physiology, Nitric Oxide Synthase, Gene Targeting, Cardiovascular Diseases, Cell Cycle Proteins, Physiological Genomics, Clinical Trials as Topic, Genetic Therapy, and Vascular endothelial growth factors
The aim of this study was to develop an efficient method for packaging and concentrating lentiviral vectors that consistently yields high-titer virus on a scale suitable for in vivo applications. Transient cotransfection of 293T packaging... more
The aim of this study was to develop an efficient method for packaging and concentrating lentiviral vectors that consistently yields high-titer virus on a scale suitable for in vivo applications. Transient cotransfection of 293T packaging cells with DNA plasmids encoding lentiviral vector components was optimized using SuperFect, an activated dendrimer-based transfection reagent. The use of SuperFect allowed reproducible and efficient production of high-titer lentiviral vector at concentrations greater than 1 x 10(7) transducing units per ml (TU/ml) and required less than one-third of the total amount of DNA used in traditional calcium phosphate transfection methods. Viral titers were further increased using a novel concentration protocol that yielded an average final titer of 1.4 x 10(10) TU/ml. Lentiviruses produced using these methods exhibited efficient transduction of central nervous system and peripheral tissues in vivo. The method is reproducible and can be scaled up to facil...
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Emerging evidences indicate that diminished activity of the vasoprotective axis of the renin-angiotensin system, constituting angiotensin-converting enzyme 2 (ACE2) and its enzymatic product, angiotensin-(1-7) [Ang-(1-7)] contribute to... more
Emerging evidences indicate that diminished activity of the vasoprotective axis of the renin-angiotensin system, constituting angiotensin-converting enzyme 2 (ACE2) and its enzymatic product, angiotensin-(1-7) [Ang-(1-7)] contribute to the pathogenesis of pulmonary hypertension (PH). However, long-term repetitive delivery of ACE2 or Ang-(1-7) would require enhanced protein stability and ease of administration to improve patient compliance. Chloroplast expression of therapeutic proteins enables their bioencapsulation within plant cells to protect against gastric enzymatic degradation and facilitates long-term storage at room temperature. Besides, fusion to a transmucosal carrier helps effective systemic absorption from the intestine on oral delivery. We hypothesized that bioencapsulating ACE2 or Ang-(1-7) fused to the cholera nontoxin B subunit would enable development of an oral delivery system that is effective in treating PH. PH was induced in male Sprague Dawley rats by monocrota...
Research Interests: Pharmacology, Medicine, Pulmonary Hypertension, Hypertension, Blood Pressure, and 12 moreRenin Angiotensin Aldosterone System, Animals, Male, Clinical Sciences, Rats, Combination drug therapy, Angiotensin Converting Enzyme, Angiotensin II, Drug Carriers, Chloroplasts, Antihypertensive agents, and Cardiovascular medicine and haematology
The renin-angiotensin system plays a crucial role in the development and establishment of the hypertensive state in the spontaneously hypertensive (SH) rat. Interruption of this system's activity by pharmacological means results in... more
The renin-angiotensin system plays a crucial role in the development and establishment of the hypertensive state in the spontaneously hypertensive (SH) rat. Interruption of this system's activity by pharmacological means results in the lowering of blood pressure (BP) and control of hypertension. However, such means are temporary and require the continuous use of drugs for the control of this pathophysiological state. Our objective in this investigation was to determine if a virally mediated gene-transfer approach using angiotensin type 1 receptor antisense (AT1R-AS) could be used to control hypertension on a long-term basis in the SH rat model of human essential hypertension. Injection of viral particles containing AT1R-AS (LNSV-AT1R-AS) in 5-day-old rats resulted in a lowering of BP exclusively in the SH rat and not in the Wistar Kyoto normotensive control. A maximal anti-hypertensive response of 33 +/- 5 mmHg was observed, was maintained throughout development, and still persi...
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Angiotensin II (Ang II) type 1 receptor blocking drugs have been shown to inhibit the growth of prostate cancer cells and delay the development of prostate cancer. Functional Ang II type 2 receptors (AT2R) are present in these cells and... more
Angiotensin II (Ang II) type 1 receptor blocking drugs have been shown to inhibit the growth of prostate cancer cells and delay the development of prostate cancer. Functional Ang II type 2 receptors (AT2R) are present in these cells and inhibit growth induced by epidermal growth factor. The present studies report apoptosis of prostate cancer cells induced by AT2R overexpression. A recombinant adenoviral vector expressing AT2R (Ad-G-AT2R-EGFP) was transduced into prostate cancer cells, including androgen-independent (DU145 and PC3) and androgen-dependent cell lines (LNCaP). Following AT2R transduction, apoptosis was analyzed by terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling staining and caspase-3 activity assays. The results indicate that increased expression of AT2R alone induced apoptosis in the prostate cancer lines, an effect that did not require Ang II. AT2R overexpression in DU145 cells induced inhibition of proliferation, a significant reduction of S-pha...
Research Interests: Biology, Cell Cycle, Prostate Cancer, Cancer Research, Apoptosis, and 15 moreMedicine, RNA interference, Cell line, Humans, Male, Caspase, Du, Cancer Cell, Cell Proliferation, Molecular Cancer Therapeutics, Angiotensin II, LNCaP, reverse transcriptase polymerase chain reaction, Prostatic neoplasms, and Pharmacology and pharmaceutical sciences
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Accumulating evidence indicates a key role of inflammation in hypertension and cardiovascular disorders. However, the role of inflammatory processes in neurogenic hypertension remains to be determined. Thus, our objective in the present... more
Accumulating evidence indicates a key role of inflammation in hypertension and cardiovascular disorders. However, the role of inflammatory processes in neurogenic hypertension remains to be determined. Thus, our objective in the present study was to test the hypothesis that activation of microglial cells and the generation of proinflammatory cytokines in the paraventricular nucleus (PVN) contribute to neurogenic hypertension. Intracerebroventricular infusion of minocycline, an anti-inflammatory antibiotic, caused a significant attenuation of mean arterial pressure, cardiac hypertrophy, and plasma norepinephrine induced by chronic angiotensin II infusion. This was associated with decreases in the numbers of activated microglia and mRNAs for interleukin (IL) 1β, IL-6, and tumor necrosis factor-α, and an increase in the mRNA for IL-10 in the PVN. Overexpression of IL-10 induced by recombinant adenoassociated virus-mediated gene transfer in the PVN mimicked the antihypertensive effects ...
Research Interests: Endocrinology, Cytokines, Inflammation, Immunohistochemistry, Medicine, and 15 moreBrain, Internal Medicine, Hypertension, Blood Pressure, Animals, Microglia, Gene transfer techniques, Male, Heart rate, Clinical Sciences, Rats, Angiotensin II, Minocycline, Interleukin, and Cardiovascular medicine and haematology
Research Interests: Treatment, Treatment Outcome, Risk assessment, Cardiovascular disease, Medicine, and 15 morePrevention, Humans, Hypertension, Renin Angiotensin Aldosterone System, Female, Animals, Male, Clinical Sciences, Prognosis, Cardiovascular Diseases, Risk Assessment, Angiotensin Converting Enzyme Inhibitors, Severity of Illness Index, Cardiovascular medicine and haematology, and Angiotensin
Hypertension is a debilitating disease with significant socioeconomic and emotional impact. Despite recent success in the development of traditional pharmacotherapy for the management of hypertension, the incidence of this disease is on... more
Hypertension is a debilitating disease with significant socioeconomic and emotional impact. Despite recent success in the development of traditional pharmacotherapy for the management of hypertension, the incidence of this disease is on the rise and has reached epidemic proportions by all estimates. This has led many to conclude that traditional pharmacotherapy has reached an intellectual plateau, and novel approaches for the treatment and control of hypertension must be explored. We have begun to investigate the possibility of treating and/or curing hypertension by using genetic means. In this review, we will provide evidence in favor of targeting of the renin-angiotensin system by antisense gene therapy as an effective strategy for the lifelong prevention of hypertension in the spontaneously hypertensive rat model. In addition, we will discuss the properties of an ideal vector for the systemic delivery of genes and the potential experimental hurdles that must be overcome to take t...
Research Interests: Medicine, HIV, Humans, Hypertension, Mutation, and 15 moreGenetic Enhancement, Blood Pressure, Animals, Disease, Peptides, Clinical Sciences, Pharmacotherapy, Rats, Nitric Oxide Synthase, Intensive Care Medicine, Angiotensin II, Atrial Natriuretic Factor, Adrenomedullin, Genetic Therapy, and Cardiovascular medicine and haematology
The role of the angiotensin II type-2 receptor (AT 2 R) in cardiac hypertrophy remains elusive despite its demonstrated involvement in cardiovascular development. We have previously shown that a lentiviral vector gene delivery system is... more
The role of the angiotensin II type-2 receptor (AT 2 R) in cardiac hypertrophy remains elusive despite its demonstrated involvement in cardiovascular development. We have previously shown that a lentiviral vector gene delivery system is able to transduce cardiac tissue with high efficiency in vivo. Using such an approach, our objectives in the present study were 2-fold: (1) to overexpress the AT 2 R in cardiac tissue after completion of natural embryonic development of the heart and (2) to determine the effects of this overexpression on cardiac hypertrophy and basal blood pressure (BP). A lentiviral vector encoding the AT 2 R (lenti-AT 2 R) was administered (1.5×10 8 transducing units) into the left ventricular space of 5-day-old spontaneously hypertensive rats (SHRs). AT 2 R transgene expression increased in these animals and persisted for 30 weeks. In contrast, the expression of the angiotensin II type-1 receptor remained unchanged following lenti-AT 2 R treatment. At 21 weeks fol...
Research Interests: Endocrinology, Biology, Cardiac Hypertrophy, Blood Pressure, Animals, and 15 moreHeart, Fibrosis, Antagonist, Genes, Clinical Sciences, Gene Delivery, Embryonic Development, Body Weight, Angiotensin II, Heart Ventricles, Gene Transfer, Cardiomegaly, CHO cells, Cricetinae, and Cardiovascular medicine and haematology
In spite of recent advancements in the treatment of pulmonary hypertension, successful control has yet to be accomplished. The abundant presence of angiotensin-converting enzyme 2 (ACE2) in the lungs and its impressive effect in the... more
In spite of recent advancements in the treatment of pulmonary hypertension, successful control has yet to be accomplished. The abundant presence of angiotensin-converting enzyme 2 (ACE2) in the lungs and its impressive effect in the prevention of acute lung injury led us to test the hypothesis that pulmonary overexpression of this enzyme could produce beneficial outcomes against pulmonary hypertension. Monocrotaline (MCT) treatment of mice for 8 weeks resulted in significant increases in right ventricular systolic pressure, right ventricle:left ventricle plus septal weight ratio, and muscularization of pulmonary vessels. Administration of a lentiviral vector containing ACE2, 7 days before MCT treatment prevented the increases in right ventricular systolic pressure (control: 25±1 mm Hg; MCT: 44±5 mm Hg; MCT+ACE2: 26±1 mm Hg; n=6; P <0.05) and right ventricle:left ventricle plus septal weight ratio (control: 0.25±0.01; MCT: 0.31±0.01; MCT+ACE2: 0.26±0.01; n=8; P <0.05). A signif...
Research Interests: Gene Therapy, Medicine, Prevention, Pulmonary Hypertension, Probability, and 15 moreHypertension, Mice, Animals, Gene transfer techniques, Male, Lung, Clinical Sciences, Analysis of Variance, Cardiovascular Diseases, Pulmonary, Angiotensin Converting Enzyme, Gene Transfer, Cardiovascular medicine and haematology, monocrotaline, and Angiotensin
Angiotensin-converting enzyme 2 (ACE2) plays a critical role against myocardial infarction (MI). We hypothesized that activation of intrinsic ACE2 would be protective against ischemia-induced cardiac pathophysiology. Diminazene aceturate... more
Angiotensin-converting enzyme 2 (ACE2) plays a critical role against myocardial infarction (MI). We hypothesized that activation of intrinsic ACE2 would be protective against ischemia-induced cardiac pathophysiology. Diminazene aceturate (DIZE), a small molecule ACE2 activator, has been used to evaluate this hypothesis. DIZE (15 mg/kg per day, s.c.) was injected 2 days before MI surgery and continued throughout the study period. MI rats showed a 62% decrease in fractional shortening (%; control, 51.1±3.2; DIZE alone, 52.1±3.2; MI, 19.1±3.0), a 55% decrease in contractility (dP/dt max mm Hg/s; control, 9480±425.3; DIZE alone, 9585±597.4; MI, 4251±657.7), and a 27% increase in ventricular hypertrophy (mg/mm; control, 26.5±1.5; DIZE alone, 26.9±1.4; MI, 33.4±1.1). DIZE attenuated the MI-induced decrease in fractional shortening by 89%, improved dP/dt max by 92%, and reversed ventricular hypertrophy by 18%. MI also significantly increased ACE and angiotensin type 1 receptor levels but d...