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Anti-Fibrotic Effects of Class I HDAC Inhibitor, Mocetinostat Is Associated with IL-6/Stat3 Signaling in Ischemic Heart Failure

Cardiovascular Research Laboratory, Banner Sun Health Research Institute, Sun City, AZ 85351, USA
Author to whom correspondence should be addressed.
Academic Editor: H. W. M. Niessen
Int. J. Mol. Sci. 2015, 16(5), 11482-11499;
Received: 9 March 2015 / Revised: 26 April 2015 / Accepted: 5 May 2015 / Published: 19 May 2015
(This article belongs to the Special Issue Improvement of Cardiac Function in Heart Failure)
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Background: Recent studies have linked histone deacetylases (HDAC) to remodeling of the heart and cardiac fibrosis in heart failure. However, the molecular mechanisms linking chromatin remodeling events with observed anti-fibrotic effects are unknown. Here, we investigated the molecular players involved in anti-fibrotic effects of HDAC inhibition in congestive heart failure (CHF) myocardium and cardiac fibroblasts in vivo. Methods and Results: MI was created by coronary artery occlusion. Class I HDACs were inhibited in three-week post MI rats by intraperitoneal injection of Mocetinostat (20 mg/kg/day) for duration of three weeks. Cardiac function and heart tissue were analyzed at six week post-MI. CD90+ cardiac fibroblasts were isolated from ventricles through enzymatic digestion of heart. In vivo treatment of CHF animals with Mocetinostat reduced CHF-dependent up-regulation of HDAC1 and HDAC2 in CHF myocardium, improved cardiac function and decreased scar size and total collagen amount. Moreover, expression of pro-fibrotic markers, collagen-1, fibronectin and Connective Tissue Growth Factor (CTGF) were reduced in the left ventricle (LV) of Mocetinostat-treated CHF hearts. Cardiac fibroblasts isolated from Mocetinostat-treated CHF ventricles showed a decrease in expression of collagen I and III, fibronectin and Timp1. In addition, Mocetinostat attenuated CHF-induced elevation of IL-6 levels in CHF myocardium and cardiac fibroblasts. In parallel, levels of pSTAT3 were reduced via Mocetinostat in CHF myocardium. Conclusions: Anti-fibrotic effects of Mocetinostat in CHF are associated with the IL-6/STAT3 signaling pathway. In addition, our study demonstrates in vivo regulation of cardiac fibroblasts via HDAC inhibition. View Full-Text
Keywords: congestive heart failure; myocardial infarction; Mocetinostat; cardiac fibrosis; HDAC congestive heart failure; myocardial infarction; Mocetinostat; cardiac fibrosis; HDAC

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Nural-Guvener, H.; Zakharova, L.; Feehery, L.; Sljukic, S.; Gaballa, M. Anti-Fibrotic Effects of Class I HDAC Inhibitor, Mocetinostat Is Associated with IL-6/Stat3 Signaling in Ischemic Heart Failure. Int. J. Mol. Sci. 2015, 16, 11482-11499.

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