Although heart failure is inevitable disease, its management depends on the understanding of the mechanism of ailing to failing myocardium. During heart failure, the heart undergoes compensatory remodeling (i.e. left ventricle hypertrophy (LVH) and vascular angiogenesis. Unfortunately, during end-stage heart failure there is dis-coordination between the LVH and angiogenesis (i.e. LVH persists but angiogenesis declines). This leads to continue increase in LV wall stress, leading to failure. Remodeling by its very nature implies synthesis, degradation, and re-arrangement of intra and inter cellular matrix. Matrix metalloproteinases (MMPs) are designer, architecture and tailor. The long-term goal of this project is to understand the differential role of MMPs in structural and functional heterogeneity in myocardial remodeling. The selective MMP-2 gene ablation reduces survival and exacerbates cardiac failure-induced by myocardial inflammation. MMP-9 gene ablation is cardioprotective. In human heart end-stage failure MMP-9 activation supersedes the MMP-2 activation. The hypothesis of this proposal is that MMP-2 is constitutive and during compensatory phase activates proteinase activated receptor-1 (PAR-1, a GPCR) and releases growth factors via the activation of anti-stress (PKB/AKT). Chronic stress leads to mitochondrial mitophagy and activation of MMP-9 and MMP-13 (an interstitial collagenase in rodent and MMP-1 in human). TIMP-3 (an apoptotic/autophagic factor) and anti-angiogenic statins are released, The hypothesis will be tested by following three specific aims:
Specific Aim #1 : To determine whether the induction of MMP-2, PAR-1, G1s, and AKT causes compensatory hypertrophy and mitochondrial mitophagy causes MMP-9 activation and decreases G1s and AKT in de-compensatory heart failure.
Specific Aim #2 : To determine whether the MMP-2 releases angiogenic growth factors during compensatory remodeling and MMP-9 releases anti-angiogenic statins in de-compensatory heart failure.
Specific Aim #3 : To determine whether the mitochondrial mitophagy attenuates angiogenesis, in part, by activating MMP-9, releasing TIMP-3 and generating statins during de-compensatory heart failure. These studies will delineate the causative role of PAR-1, MMP, TIMP, G1s and mitophagy in switch from compensatory LVH and angiogenesis to de-compensatory LVH and anti-angiogenesis and will have therapeutic ramifications for chronic heart failure.

Public Health Relevance

These studies will delineate the differential role of mitochondrial mitophagy and anti- angiogenesis mechanisms in end-stage heart failure. The differential role of different MMPs in angiogenesis and anti-angiogenesis in transition from compensatory hypertrophy to de-compensatory heart failure will be determined. The positive outcome of this project will have therapeutic ramifications for chronic heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL108621-03
Application #
8403722
Study Section
Special Emphasis Panel (ZRG1-VH-B (02))
Program Officer
Adhikari, Bishow B
Project Start
2011-04-15
Project End
2015-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
3
Fiscal Year
2013
Total Cost
$357,000
Indirect Cost
$119,000
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 (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
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
Winchester, Lee; Veeranki, Sudhakar; Givvimani, Srikanth et al. (2014) Exercise mitigates the adverse effects of hyperhomocysteinemia on macrophages, MMP-9, skeletal muscle, and white adipocytes. Can J Physiol Pharmacol 92:575-82
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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