Abstract
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.
Highlights
After myocardial infarction (MI), there are several adaptive and maladaptive processes that occur in the heart leading to heart failure
We recently showed that inhibition of class I histone deacetylases (HDAC) with Mocetinostat reduced cardiac fibrosis in congestive heart failure (CHF) hearts and diminished cardiac myofibroblast activation [8]
We investigated whether beneficial effects of HDAC inhibition on CHF rats would further increase with a new dose of Mocetinostat (20 mg/kg/day)
Summary
After myocardial infarction (MI), there are several adaptive and maladaptive processes that occur in the heart leading to heart failure. We recently showed that inhibition of class I HDACs with Mocetinostat reduced cardiac fibrosis in CHF hearts and diminished cardiac myofibroblast activation [8]. Inhibition of class 1 and 2 HDACs resulted in reduction of circulating levels of several pro-inflammatory cytokines including IL-6 in rats with induced hypertensive cardiomyopathy [4]. It is unclear whether anti-fibrotic effects of HDAC inhibition in CHF are associated with modulation of pro-inflammatory cytokines. The anti-fibrotic activity of Mocetinostat includes modulation of IL-6/STAT3 axis and down-regulation of ECM production in myocardium and cardiac fibroblasts in vivo
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