Histone deacetylase inhibition improved cardiac functions with direct antifibrotic activity in heart failure.
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.
Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Yu-Hsun
YH
Kao
Jing-Ping
JP
Liou
Cheng-Chich
CC
Chung
Gi-Shih
GS
Lien
Ching-Chuan
CC
Kuo
Shih-Ann
SA
Chen
Yi-Jen
YJ
Chen
D000818:Animals; D000933:Antifibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D006333:Heart Failure / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar
D000933:Antifibrinolytic Agents; D056572:Histone Deacetylase Inhibitors
Angiotensin II type I receptor; Fibroblast; Heart failure; Histone deacetylases; Transforming growth factor-β