The focus of my reseach is to evaluate the mechanisms underlying vascular dysfunction seen in hypoxia and pulmonary hypertension utilizing in vivo, ex vivo, molecular biology and electrohysiological approaches. Specifically, we are interested in understanding the role of natriuretic peptides in hypoxia mediated endothelial dysfunction.

Biography

Dr. Choudhary is an Assistant Professor of Medicine and staff cardiologist at the Providence VA Medical Center. He went to All India Insttitue of Medical Sciences for medical school and University of Illinois at Chicago/ Michael Reese Hospital for residency in Internal Medicine. He did his cardiovascular diseases fellowship from Emory University, Atlanta from 2000-2004. He spent two years with Dr. Samuel Dudley as post-doctoral fellow during his fellowship. He was appointed Assistant Professor at Brown University in 2004. Dr. Choudhary's reseach is performed at the Vascular Research Laboratory.

Institutions

VMAC

Research Description

Role of C-type Natriuretic Peptide in Pulmonary Vascular Function
Hypoxia causes endothelial barrier dysfunction and is a pro-proliferative and pro-inflammatory stimulus. Endothelial dysfunction induced by hypoxia can exacerbate inflammatory lung diseases and contribute to pulmonary arterial hypertension (PAH). In animal models, hypoxia has been shown to exacerbate lipopolysaccharide-induced lung injury and oxygen supplementation reduces right ventricular hypertrophy, vascular remodeling and RV peak pressure in monocrotaline-injected rats. Hypoxia shares some common pathways of vascular remodeling with monocrotaline through HIF-1. Amelioration of the deleterious effects of hypoxia on pulmonary microvascular endothelium may reduce the morbidity associated with inflammatory lung diseases, such as ARDS.
The main hypothesisis that CNP blunts hypoxia induced pulmonary vascular dysfunction by modulating endothelial cell membrane potential and attenuating hypoxia induced endothelial monolayer permeability and its effect on release of inflammatory and mitogenic mediators from endothelium.
Aim 1:We will determine the effect of CNP on the membrane potential of hypoxic and normoxic lung microvascular endothelial cells (LMVEC) and evaluate the underlying mechanism(s) involved.
Aim 2:We will determine the effects of CNP on barrier function of normoxic and hypoxic LMVECs.
Aim 3: We will determine the effects of CNP on the production and secretion of inflammatory and mitogenic mediators in LMVEC in hypoxia.
Our preliminary studies have shown that CNP causes membrane potential changes,improved monolayer permeability and is an anti-proliferative stimulus.
These studies will determine the effects of CNP on pulmonary endothelial dysfunction associated with hypoxia, and will serve as the foundation for animal and translational studies on prevention of lung vascular injury and pulmonary arterial hypertension. Development of agents that blunt the injurious effects of hypoxia on the pulmonary circulation is highly likely to improve the course and prognosis of pulmonary arterial hypertension and acute respiratory distress syndrome (ARDS), common diseases among veterans. Exacerbation of lung injury and edema in hypoxia is also commonly seen in intensive care units in the VA medical centers. In high altitudes, development of lung edema is a common and disabling problem for veterans and our troops. The results from these studies will help us in understanding the potential role of this novel therapeutic strategy in preventing some of these disorders.

Role of Endothelin-Induced PKC delta Activation in Right Ventricular Hypertrophy.
Maladaptive hypertrophic changes in the right ventricle (RV) are the primary cause of morbidity and mortality in patients with pulmonary arterial hypertension (PAH). RV hypertrophy (RVH) usually progress to myocardial apoptosis and fibrosis, resulting in RV dilation, hypokinesis, and eventually RV failure and death. Both endothelin (ET) and protein kinase C (PKC) have been shown to be involved in the pathophysiology of RVH in animal models. ET-mediated PKC activation, particularly the α and δ isoforms, has been demonstrated in cardiomyocytes. Recent studies, have found that PKCδ has the greatest increase in RV PKC activity in response to pulmonary artery banding, suggesting the importance of this isoform in RVH.
We hypothesize that ET-1 induces pathologic hypertrophic changes in the RV by activating PKCδ. We aim to determine if bosentan mitigates maladaptive hypertrophic responses in the RV by inhibiting PKCδ expression and/or activity that in turn may attenuate myocardial apoptosis, fibrosis and decreased contractility. Two models of RVH are being studied, one with pulmonary hypertension (chronic hypoxia) and another with increased RV afterload in the absence of pulmonary hypertension (PA banding).

Awards

2008 Northwestern University Young Investigators' Forum- Third Prize
2008 Actelion Pharmaceuticals Young Investigator Award
2008 Member: AHA Peer Review Committee (Region I)
2007 Member, AHA NE Affiliate Peer-Review Committee
2006 Dean's Teaching Excellence Award, Brown Medical School
2006 Fellow of American College of Cardiology
2001 Pfizer Travel Award for American Heart Association Meeting, 2001
2000 Heart Failure Society Travel Award
Reviewer: Nature Clinical Practice Cardiovascular Medicine, Atherosclerosis Thrombosis and Vascular Biology, Lung, Journal of Respiratory Diseases

Affiliations

2008-Present Member, Peer-review Committee, Providence VAMC
2006- 2008 Member, Curriculum Redesign Committee- IT Working
Group, Brown Medical School
2005- Present Associate Char, Research & Development Committee,
Providence VA Medical Center, Providence, RI
2005- Present Member, Advanced Clinic Access Committee, RI
Providence VA Medical Center, Providence,
2007 Biophysical Society
2001 American Heart Association Basic Science Council
2001 American College of Cardiology

Funded Research

2005-2006
Rhode Island Foundation: Medical Research Award
Project: Role of C-type Natriuretic Peptide in Pulmonary Vascular Function
Role: Principal Investigator


2006-2007
RI-INBRE Proposal Development Pilot Project (Choudhary)
Project: Role of C-type Natriuretic peptide in microvascular endothelial cell proliferation and apoptosis
Role: Principal Investigator


2007-2010
Career Development Award, Department of Veterans Affairs (Choudhary)
Project: Role of C-type Natriuretic Peptide in Pulmonary Vascular Function
Role: Principal Investigator

2008
Actelion Young Investigator Award (Choudhary)
Project: Role of Endothelin-Induced PKC delta Activation in Right Ventricular Hypertrophy.
Role: Principal Investigator

Teaching Experience

WebCT Course
Learning to read an electrocardiogram

Courses Taught

• Cardiac Pathophysiology/Pharmacology (IMS 350)
• Cardiology Elective (314)
• Mechanisms of Vascular Injury (Bio 284)

Selected Publications

• • Change in Hemoglobin A1C and C-Reactive Protein Levels in Patients with Diabetes Mellitus. Khatana S.A.M., Taveira T.H., Choudhry G., Eaton C.H., Wu W-C. Cardiometab Syndr. 2009 Spring;4(2):76-80(2009)
• • Mechanism of C-type Natriuretic Peptide-Induced Endothelial Cell Hyperpolarization. Aaron Simon, Elizabeth Harrington, GongXin Liu, Gideon Koren, Gaurav Choudhary. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2009 Feb;296(2):L248-56.(2009)
• • cANF Causes Endothelial Cell Hyperpolarization By Activation of Chloride Channels. Aaron Simon, Gong-Xin Liu, Gideon Koren, Gaurav Choudhary. Peptides. 2009. In Press.(2009)
• • Rottlerin causes Pulmonary Edema in vivo: A Possible Role for PKCδ. James R. Klinger, Josh D. Murray, Brian Casserly, Diego F. Alvarez, Judy A. King, Steven S. An, Gaurav Choudhary, Akua Owusu-Sarfo, Rod Warburton, and Elizabeth O. Harrington. Appl Physiol. 2007 Dec;103(6):2084-94.(2007)
• • Docking of Conotoxin GIIIA in Voltage-gated Sodium Channel. Gaurav Choudhary, Marcela Aliste, Peter Tieleman, Robert J. French, Samuel C. Dudley. Channels, 2007 Sep-Oct; 1(5):344-352(2007)
• • Atrial Fibrillation. Ohad Ziv and Gaurav Choudhary Prim Care. 2005 Dec;32(4):1083-107(2005)
• • Pneumopericardium And Pneumothorax After Permanent Pacemaker Implantation. Clifford C. Sebastian, M.D.; Wen-Chih Wu, M.D.; Mark Shafer, M.D.; Gaurav Choudhary, M.D., Pranav M. Patel, M.D. Pacing Clin Electrophysiol. 2005 May;28(5):466-8.(2005)
• • Flow Mediated Vasodilation Predicts the Presence and Extent of Coronary Disease Assessed by Stress Thallium Imaging. Wen-Chih Wu, MD; Satish C. Sharma, MD, FACC; Gaurav Choudhary, MD; Linda Coulter, RN; Elizabeth Coccio, RN; and Charles B. Eaton, MD, FAHA. Journal of Nuclear Cardiology. 2005 Sep-Oct;12(5):538-44(2005)
• • The structure of zetekitoxin AB, a saxitoxin analog from the Panamanian golden frog Atelopus zeteki: a potent sodium-channel blocker. Yotsu-Yamashita M, Kim YH, Dudley SC Jr, Choudhary G, Pfahnl A, Oshima Y, Daly JW. Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4346-51. Epub 2004 Mar 22.(2004)
• • Interaction of C-11 hydroxyl of Tetrodotoxin with the Sodium Channel Outer Vestibule. Gaurav Choudhary, Mari Yotsu-Yamashita, Lisa Shang, Takeshi Yasumoto, Samuel C. Dudley, Jr. Biophysical Journal 2003. Jan;84(1):287-94(2003)
• • Heart Failure, Oxidative Stress and Ion Channel Modulation. Gaurav Choudhary, Samuel C Dudley, Jr. Congestive Heart Failure. 2002; 8:148-155.(2002)
• • Energetic Localization of Saxitoxin in its Channel Binding Site. Gaurav Choudhary, Lisa Shang, Xiufeng Li, Samuel C. Dudley, Jr. Biophysical Journal. 2002; 83: 912-919.(2002)
• • Carvedilol Titration in Patients with Congestive Heart Failure Receiving Inotropic Therapy. Ananth N Kumar, Gaurav Choudhary, Cindy Antonio, Vicki Just, Ajay Jain, Lori Heaney Mary Ann Papp. Am Heart J. 2001 Sep;142(3):512-5.(2001)
• • Apoptosis of Lung Epithelial Cells in Response to TNF-α Requires Angiotensin II Generation de Novo. Rongqi Wang, Golam Alam, Alex Zagariya, Claudia Gidea, Hugo Pillinois, Omasalewa Lalude, Gaurav Choudhary, Devlet Oezatalay, and Bruce D Uhal. J Cell Phys. 2000 Nov; 185(2): 253-9.(2000)
• • Angiotensin II Induces Apoptosis in Human and Rat Alveolar Epithelial Cells. Wang R, Zagariya A, Ibarra-Sunga O, Gidea C, Ang E, Deshmukh S, Choudhary G, Baraboutis J, Filippatos G and Uhal BD. Am J Physiol. 1999 May;276(5 Pt 1):L885-9.(1999)