Abstract

Background Histone deacetylases (HDACs), important epigenetic regulatory enzymes, can reduce cardiac hypertrophy and cardiac fibrosis. However, the mechanisms underlying the antifibrotic activity of HDAC inhibitors remain unclear. The purposes of this study were to evaluate the effects of an HDAC inhibitor on systolic heart failure (HF) and investigate the potential mechanisms. Methods Echocardiographic, histologic, atrial natriuretic peptide (ANP), and Western blot measurements were performed in HF rats (isoproterenol 100 mg/kg, subcutaneous injection) with and without orally administered (100 mg/kg for 7 consecutive days) MPT0E014 (a novel HDAC inhibitor). Western blot, migration and proliferation assays were carried out on primary isolated cardiac fibroblasts with and without MPT0E014 (0.1 and 1 μM) for 24 h. Results MPT0E014-treated HF rats (n = 6) had better fraction shortening (48 ± 2 vs. 33 ± 4%, p = 0.006) and smaller left ventricular end diastolic diameter (4.6 ± 0.2 vs. 5.6 ± 0.3 mm, p = 0.031) and systolic diameter (2.4 ± 0.2 vs. 3.9 ± 0.3 mm, p = 0.006) than HF (n = 7) rats. MPT0E014-treated HF rats had lower ANP, cardiac fibrosis, and angiotensin II type I receptor (AT1R), transforming growth factor (TGF)-β, and CaMKIIδ protein levels compared to HF rats. MPT0E014 (at 1 μM, but not 0.1 μM) decreased the migration and proliferation of cardiac fibroblasts. MPT0E014 (0.1 and 1 μM) decreased expression of the AT1R and TGF-β. Conclusions MPT0E014 improved cardiac contractility and attenuated structural remodeling in isoproterenol-induced dilated cardiomyopathy. The direct antifibrotic activity may have contributed to these beneficial effects.

Original languageEnglish
Pages (from-to)4178-4183
Number of pages6
JournalInternational Journal of Cardiology
Volume168
Issue number4
DOIs
Publication statusPublished - Oct 9 2013

Keywords

  • Angiotensin II type I receptor
  • Fibroblast
  • Heart failure
  • Histone deacetylases
  • Transforming growth factor-β

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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