Program Director/Principal Investigator (Last, First, Middle): Tyagi, Suresh C., The overall goal of this project is to understand the mechanism of endocardial endothelial-myocyte (E-M) dysfunction in chronic heart failure. Studies from the previous funding period suggested that endocardial endothelial dysfunction is associated with increased oxidized-matrix accumulation (fibrosis), activation of latent resident myocardial matrix metalloproteinases (MMPs) and inactivation of cardiac tissue inhibitor of metalloproteinase (TIMP-4) secondary to oxidative and proteolytic stresses. Administration of TIMP-4 ameliorated both the formation of reactive oxygen species (ROS, oxidative stress) and MMP activation (proteolytic stress). In addition, we discovered the induction of proteinase activated receptor-1 (PAR-1). However, the role of PAR-1 in fibrosis and E-M uncoupling remains poorly defined. H2S gas is the most potent antioxidant in mitigating oxidative stress and recent studies have implicated a cardioprotective role of H2S. The central hypothesis of this competitive renewal proposal is that during chronic heart failure the oxidative and proteolytic stresses induce PAR-1, leading to generate mitochondrial (mt) ROS and reactive nitrogen species (RNS) and mitochondrial nitric oxide synthase (mtNOS), respectively, thus activating the latent resident cardiac MMPs. These events disrupt the MMP/TIMP axis, causing fibrosis between endothelium and myocyte. Treatment with H2S alleviates fibrosis and mitigates E-M uncoupling. Therefore, the specific aims of this proposal are: #1: To determine whether chronic left ventricle (LV) volume overload causes mitochondrial oxidative stress (ROS and RNS) by inducing NADPH oxidase (p47 subunit), mtNOS and PAR-1, and H2S alleviates mitochondrial oxidative stress. #2: To determine whether chronic LV volume overload causes cardiac fibrosis by increasing collagen/elastin ratio, MMP-2, -9, -13, TIMP-1, -3, decreasing TIMP-4, and inducing PAR-1, and H2S mitigates cardiac fibrosis. #3: To determine whether chronic LV volume overload causes E-M dysfunction and LVH by inducing PAR-1 and H2S decreases E-M uncoupling. Chronic heart failure will be created by LV volume overload by aorta-venacava fistula (AVF) in wild type (WT), PAR-1-/+, iNOS-/-, MMP-9-/-, TIMP-3-/-, and TIMP-4++/++ mice, treated with or without NaHS, a H2S donor. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page

Public Health Relevance

Tyagi, Suresh C., The myocyte contraction and relaxation are synchronized only when myocytes are connected by extracellular matrix (ECM). We coined the term endothelial-myocyte (E-M) coupling because endocardial endothelial (EE) cells derived cardio-active agents modulate myocyte contraction in systole and relaxation in diastole. The endothelium in the heart is the least studied system, because unlike conduit arteries, the endocardial endothelium is burried in the muscle and it is difficult to separate its role in myocyte function. We developed a new techniques cardiac rings in which endothelium dependent or independent cardiac contraction and relaxation can be examined separately in LV and RV. There are two novel aspects of this proposal: 1) the proposed experiments will demonstrate the role of PAR-1 in the underlying mechanism of fibrosis and endothelial-myocyte uncoupling in heart failure;and 2) will have clinical translational ramifications of H2S in treating diastolic heart failure. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL074185-09
Application #
8267028
Study Section
Special Emphasis Panel (ZRG1-CVS-D (03))
Program Officer
Schwartz, Lisa
Project Start
2003-09-05
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
9
Fiscal Year
2012
Total Cost
$366,300
Indirect Cost
$118,800
Name
University of Louisville
Department
Physiology
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
Veeranki, Sudhakar; Tyagi, Suresh C (2016) Dysbiosis and Disease: Many Unknown Ends, Is it Time to Formulate Guidelines for Dysbiosis Research? J Cell Physiol :
Majumder, Avisek; JyotirmayaBehera; Jeremic, Navena et al. (2016) Hypermethylation: Causes and Consequences in Skeletal Muscle Myopathy. J Cell Biochem :
Soni, Chirag V; Tyagi, Suresh C; Todnem, Nathan D et al. (2016) Hyperhomocysteinemia Alters Sinoatrial and Atrioventricular Nodal Function: Role of Magnesium in Attenuating These Effects. Cell Biochem Biophys 74:59-65
Veeranki, Sudhakar; Givvimani, Srikanth; Kundu, Sourav et al. (2016) Moderate intensity exercise prevents diabetic cardiomyopathy associated contractile dysfunction through restoration of mitochondrial function and connexin 43 levels in db/db mice. J Mol Cell Cardiol 92:163-73
Chaturvedi, Pankaj; Kamat, Pradip K; Kalani, Anuradha et al. (2016) High Methionine Diet Poses Cardiac Threat: A Molecular Insight. J Cell Physiol 231:1554-61
Kunkel, George H; Chaturvedi, Pankaj; Tyagi, Suresh C (2016) Mitochondrial pathways to cardiac recovery: TFAM. Heart Fail Rev 21:499-517
Chernyavskiy, Ilya; Veeranki, Sudhakar; Sen, Utpal et al. (2016) Atherogenesis: hyperhomocysteinemia interactions with LDL, macrophage function, paraoxonase 1, and exercise. Ann N Y Acad Sci 1363:138-54
Prathipati, Priyanka; Metreveli, Naira; Nandi, Shyam Sundar et al. (2016) Ablation of Matrix Metalloproteinase-9 Prevents Cardiomyocytes Contractile Dysfunction in Diabetics. Front Physiol 7:93
Theilen, Nicholas T; Kunkel, George H; Tyagi, Suresh C (2016) The Role of Exercise and TFAM in Preventing Skeletal Muscle Atrophy. J Cell Physiol :
Kalani, Anuradha; Chaturvedi, Pankaj; Kamat, Pradip K et al. (2016) Curcumin-loaded embryonic stem cell exosomes restored neurovascular unit following ischemia-reperfusion injury. Int J Biochem Cell Biol 79:360-369

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