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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., (© 2013.)

Heart failure (HF) can increase atrial fibrillation and induce cardiac hypermethylation. The homeobox gene Pitx2c plays important roles in the genesis of atrial fibrillation and the promoter region of Pitx2c contains cytosine-phosphate-guanine islands. Therefore, epigenetic modification by hypermethylation may reduce Pitx2c expression in atrial myocytes. The aim of the present study were to evaluate whether HF can modulate DNA methylation of Pitx2c and the potential mechanisms involved. We used real-time polymerase chain reaction, immunoblotting and pyrosequencing to investigate RNA and protein expression, as well as the methylation of Pitx2c, in isoproterenol-induced HF, healthy rat left atria and in HL-1 cells with and without (control) exposure to angiotensin (Ang) II (0.1 and 1 μmol/L) or isoproterenol (1 or 10 μmol/L) for 24 h. The HF atrium exhibited increased Pitx2c promoter methylation with increased DNA methyltransferase (DNMT) 1 and decreased Pitx2c protein levels compared with the normal atrium. Angiotensin II (0.1 and 1 μmol/L), increased Pitx2c promoter methylation in HL-1 cells with increased DNMT1 and decreased Pitx2c and Kir2.1 protein levels compared with control cells. These effects were attenuated by the methylation inhibitor 5-aza-2'-deoxycytidine (0.1 μmol/L) and by the AngII receptor blocker losartan (10 μmol/L). However, isoproterenol (1 and 10 μmol/L) did not change the expression of the Pitx2c, DNMT1 and Kir2.1 proteins. In conclusion, HF induces Pitx2c promoter hypermethylation and AngII may contribute to the hypermethylation in HF., (© 2013 Wiley Publishing Asia Pty Ltd.)

Cardiovascular disease is the leading cause of morbidity and mortality in patients with diabetes mellitus (DM), and patients with DM frequently develop diabetic cardiomyopathy. Currently, effective treatments for diabetic cardiomyopathy are limited. Vitamin D exerts pleiotropic effects on the cardiovascular system and is associated with DM. The purpose of this review was to evaluate published research on vitamin D in diabetic cardiomyopathy by searching PubMed databases. Herein, we reviewed vitamin D metabolism; evaluated the molecular, cellular, and neuroendocrine effects in native and bioactive vitamin D; and evaluated the role of vitamin D in treating cardiovascular disease and DM. Some evidence suggests that vitamin D may improve cardiovascular outcomes in diabetes through anti-inflammatory, antioxidative, antihypertrophic, antifibrotic, and antiatherosclerotic activities and by regulating advanced glycation end-product signaling, the renin-angiotensin system, and cardiac metabolism. This clinical and laboratory evidence suggests that vitamin D may be a potential agent in treating diabetic cardiomyopathy. However, using vitamin D entails possible adverse risks of hypercalcemia, hyperphosphatemia, and vascular calcifications. Therefore, future studies should be conducted that clarify the potential benefits of vitamin D through large-scale randomized clinical trials in well-defined groups of diabetic patients. [ABSTRACT FROM AUTHOR]