Congestive heart failure (HF) is one of the leading causes of death and complications worldwide. Even after complete revascularization by coronary artery bypass grafting (CABG) patients with MI (myocardial infarction) often develop adverse ventricular remodeling in the remote myocardium which generates complications leading to HF. Both human and animal studies have demonstrated that biochemical and mechanical stress on the heart leads to cardiac myocyte hypertrophy and cardiac fibroblasts (CF) differentiation to myofibroblasts (myoFB) which deposit extracellular matrix (ECM), leading to adverse ventricular remodeling. The underlying mechanism of CF transformation to myoFB is not yet fully understood. New approaches are needed to define the mechanism behind this pathological process, and to identify new therapeutic strategies to protect the heart from descending to failure post MI. My laboratory has specific interest in sirtuins, which are capable of activating intracellular anti-oxidant defense mechanisms and extending life-span of species. Recent work from my laboratory has identified one sirtuin isoform, SIRT3 as an endogenous negative regulator of cardiac hypertrophy. SIRT3-deficent mice develop cardiac hypertrophy associated with interstitial fibrosis, and transgenic mice with cardiac-specific over expression of SIRT3 are protected from developing hypertrophy. We also found that SIRT3 (-/-) fibroblasts are highly permissive to myoFB transformation, but not the fibroblasts over expressed with SIRT3. Additional studies done with human hearts showed that SIRT3 levels are dramatically reduced in patients with ischemic cardiomyopathy, and over expression of SIRT3 blocks pro-fibrotic effects of Ang-II on human CF in vitro. Based on these findings we hypothesized that loss of SIRT3 may be a cause of CF transformation to myoFB, and thus by maintaining cellular SIRT3 levels CF differentiation to myoFB can be blocked, and heart could be protected from developing fibrosis and HF. To test this hypothesis we propose three specific aims: (1) Study the role of SIRT3 in regulating adult human CF transformation to myoFB and the maladaptive cardiac remodeling. (2) Determine underlying mechanisms through which SIRT3 blocks human CF proliferation and transformation. (3) Test whether SIRT3 activation can be used as a novel therapeutic strategy to block maladaptive LV remodeling following MI in an animal model. A successful outcome of these three aims will have major impact on our understanding of the disease process of ventricular remodeling, and that this may guide us to identify new therapeutic targets critical for translational medicine of HF.

Public Health Relevance

Lay man narrative: SIRT3 is a longevity factor. It has been implicated in extending lifespan of humans. We are working on SIRT3 for nearly 7 years and have shown that increased levels of SIRT3 protect the mouse heart from cardiac hypertrophy and interstitial fibrosis. In this proposal we will test the hypothesis whether SIRT3 activation ca block development of cardiac fibrosis and adverse ventricular remodeling in post MI patients undergone coronary bypass surgery. A successful outcome of this project may guide us to develop new therapeutic strategies to treat heart failure and to mange other organ disorders associated with enhanced tissue fibrosis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Wong, Renee P
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University of Chicago
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Pillai, Vinodkumar B; Kanwal, Abhinav; Fang, Yong Hu et al. (2017) Honokiol, an activator of Sirtuin-3 (SIRT3) preserves mitochondria and protects the heart from doxorubicin-induced cardiomyopathy in mice. Oncotarget 8:34082-34098
Bindu, Samik; Pillai, Vinodkumar B; Kanwal, Abhinav et al. (2017) SIRT3 blocks myofibroblast differentiation and pulmonary fibrosis by preventing mitochondrial DNA damage. Am J Physiol Lung Cell Mol Physiol 312:L68-L78
Samant, Sadhana A; Kanwal, Abhinav; Pillai, Vinodkumar B et al. (2017) The histone deacetylase SIRT6 blocks myostatin expression and development of muscle atrophy. Sci Rep 7:11877
Pillai, Vinodkumar B; Bindu, Samik; Sharp, Will et al. (2016) Sirt3 protects mitochondrial DNA damage and blocks the development of doxorubicin-induced cardiomyopathy in mice. Am J Physiol Heart Circ Physiol 310:H962-72
Bindu, Samik; Pillai, Vinodkumar B; Gupta, Mahesh P (2016) Role of Sirtuins in Regulating Pathophysiology of the Heart. Trends Endocrinol Metab 27:563-573
Akamata, Kaname; Wei, Jun; Bhattacharyya, Mitra et al. (2016) SIRT3 is attenuated in systemic sclerosis skin and lungs, and its pharmacologic activation mitigates organ fibrosis. Oncotarget 7:69321-69336
Sundaresan, Nagalingam R; Bindu, Samik; Pillai, Vinodkumar B et al. (2015) SIRT3 Blocks Aging-Associated Tissue Fibrosis in Mice by Deacetylating and Activating Glycogen Synthase Kinase 3?. Mol Cell Biol 36:678-92
(2015) HDAC3-dependent reversible lysine acetylation of cardiac myosin heavy chain isoforms modulates their enzymatic and motor activity. J Biol Chem 290:6009
Hu, Shuqun; Liu, Hua; Ha, Yonju et al. (2015) Posttranslational modification of Sirt6 activity by peroxynitrite. Free Radic Biol Med 79:176-85
Pillai, Vinodkumar B; Samant, Sadhana; Sundaresan, Nagalingam R et al. (2015) Honokiol blocks and reverses cardiac hypertrophy in mice by activating mitochondrial Sirt3. Nat Commun 6:6656

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