Article ; Online: Anti-Fibrotic Effects of Class I HDAC Inhibitor, Mocetinostat Is Associated with IL-6/Stat3 Signaling in Ischemic Heart Failure.
International journal of molecular sciences
2015 Volume 16, Issue 5, Page(s) 11482–11499
Abstract: ... Anti-fibrotic effects of Mocetinostat in CHF are associated with the IL-6/STAT3 signaling ... fibrotic effects of HDAC inhibition in congestive heart failure (CHF) myocardium and cardiac fibroblasts ... Background: Recent studies have linked histone deacetylases (HDAC) to remodeling of the heart and ...
| 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. |
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| MeSH term(s) | Animals ; Benzamides/pharmacology ; Cicatrix ; Collagen/metabolism ; Connective Tissue Growth Factor/genetics ; Connective Tissue Growth Factor/metabolism ; Disease Models, Animal ; Fibroblasts/drug effects ; Fibroblasts/metabolism ; Fibronectins/metabolism ; Fibrosis ; Gene Expression ; Heart Failure/etiology ; Heart Failure/metabolism ; Heart Failure/pathology ; Histone Deacetylase Inhibitors/pharmacology ; Histone Deacetylases/metabolism ; Interleukin-6/metabolism ; Myocardial Ischemia/complications ; Pyrimidines/pharmacology ; Rats ; STAT3 Transcription Factor/metabolism ; Signal Transduction/drug effects ; Ventricular Function/drug effects |
| Chemical Substances | Benzamides ; Fibronectins ; Histone Deacetylase Inhibitors ; Interleukin-6 ; Pyrimidines ; STAT3 Transcription Factor ; Connective Tissue Growth Factor (139568-91-5) ; Collagen (9007-34-5) ; mocetinostat (A6GWB8T96J) ; Histone Deacetylases (EC 3.5.1.98) |
| Language | English |
| Publishing date | 2015-05-19 |
| Publishing country | Switzerland |
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2019364-6 |
| ISSN | 1422-0067 ; 1422-0067 ; 1661-6596 |
| ISSN (online) | 1422-0067 |
| ISSN | 1422-0067 ; 1661-6596 |
| DOI | 10.3390/ijms160511482 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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