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

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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

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CVS-D (03))
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Schwartz, Lisa
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University of Louisville
Schools of Medicine
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Veeranki, Sudhakar; Tyagi, Suresh C (2015) Role of hydrogen sulfide in skeletal muscle biology and metabolism. Nitric Oxide 46:66-71
Veeranki, Sudhakar; Givvimani, Srikanth; Pushpakumar, Sathnur et al. (2014) Hyperhomocysteinemia attenuates angiogenesis through reduction of HIF-1? and PGC-1? levels in muscle fibers during hindlimb ischemia. Am J Physiol Heart Circ Physiol 306:H1116-27
Tyagi, Suresh C; Joshua, Irving G (2014) Exercise and nutrition in myocardial matrix metabolism, remodeling, regeneration, epigenetics, microcirculation, and muscle. Can J Physiol Pharmacol 92:521-3
Chaturvedi, Pankaj; Tyagi, Suresh C (2014) Epigenetic mechanisms underlying cardiac degeneration and regeneration. Int J Cardiol 173:1-11
Givvimani, Srikanth; Pushpakumar, Sathnur; Veeranki, Sudhakar et al. (2014) Dysregulation of Mfn2 and Drp-1 proteins in heart failure. Can J Physiol Pharmacol 92:583-91
Givvimani, Srikanth; Narayanan, Nithya; Pushpakumar, Sathnur Basappa et al. (2014) Anti-Parstatin Promotes Angiogenesis and Ameliorates Left Ventricular Dysfunction during Pressure Overload. Int J Biomed Sci 10:1-7
Chavali, Vishalakshi; Tyagi, Suresh C; Mishra, Paras Kumar (2014) Differential expression of dicer, miRNAs, and inflammatory markers in diabetic Ins2+/- Akita hearts. Cell Biochem Biophys 68:25-35
Narayanan, Nithya; Pushpakumar, Sathnur Basappa; Givvimani, Srikanth et al. (2014) Epigenetic regulation of aortic remodeling in hyperhomocysteinemia. FASEB J 28:3411-22
Chaturvedi, Pankaj; Kalani, Anuradha; Givvimani, Srikanth et al. (2014) Differential regulation of DNA methylation versus histone acetylation in cardiomyocytes during HHcy in vitro and in vivo: an epigenetic mechanism. Physiol Genomics 46:245-55
Givvimani, S; Narayanan, N; Armaghan, F et al. (2013) Attenuation of conducted vasodilation in skeletal muscle arterioles during hyperhomocysteinemia. Pharmacology 91:287-96

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