Histone deacetylase (HDAC) inhibition improves myocardial function and prevents cardiac remodeling in diabetic mice

Abstract

BackgroundRecent evidence indicates that inhibition of histone deacetylase (HDAC) protects the heart against myocardial injury and stimulates endogenous angiomyogenesis. However, it remains unknown whether HDAC inhibition produces the protective effect in the diabetic heart. We sought to determine whether HDAC inhibition preserves cardiac performance and suppresses cardiac remodeling in diabetic cardiomyopathy.MethodsAdult ICR mice received an intraperitoneal injection of either streptozotocin (STZ, 200 mg/kg) to establish the diabetic model or vehicle to serve as control. Once hyperglycemia was confirmed, diabetic mice received sodium butyrate (1%), a specific HDAC inhibitor, in drinking water on a daily basis to inhibit HDAC activity. Mice were randomly divided into following groups, which includes Control, Control + Sodium butyrate (NaBu), STZ and STZ + Sodium butyrate (NaBu), respectively. Myocardial function was serially assessed at 7, 14, 21 weeks following treatments.ResultsEchocardiography demonstrated that cardiac function was depressed in diabetic mice, but HDAC inhibition resulted in a significant functional improvement in STZ-injected mice. Likewise, HDAC inhibition attenuates cardiac hypertrophy, as evidenced by a reduced heart/tibia ratio and areas of cardiomyocytes, which is associated with reduced interstitial fibrosis and decreases in active caspase-3 and apoptotic stainings, but also increased angiogenesis in diabetic myocardium. Notably, glucose transporters (GLUT) 1 and 4 were up-regulated following HDAC inhibition, which was accompanied with increases of GLUT1 acetylation and p38 phosphorylation. Furthermore, myocardial superoxide dismutase, an important antioxidant, was elevated following HDAC inhibition in the diabetic mice.ConclusionHDAC inhibition plays a critical role in improving cardiac function and suppressing myocardial remodeling in diabetic heart.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-015-0262-8) contains supplementary material, which is available to authorized users.

Inhibition of HDAC3 prevents diabetic cardiomyopathy in OVE26 mice via epigenetic regulation of DUSP5-ERK1/2 pathway

“…Class I, II, and IV HDACs are zinc-dependent enzymes, whereas class III HDACs, which are also known as sirtuins, require nicotinamide adenine dinucleotide (NAD + ) for catalytic activity (13). Recent studies have shown that activation of HDACs was associated with DCM since total HDAC inhibition attenuated diabetes-induced cardiac injury in the STZ-induced diabetic animal models (14, 15). In these two studies, it is unclear which specific HDAC really involves in the pathogenesis of DCM because they only used non-specific HDAC inhibitor to inhibit total HDAC activity.…”

Angiogenesis and Cardiovascular Diseases: The Emerging Role of HDACs

“…As there is evidence of genetic association between diabetes and HDACs, treatment with HDACi exerts a reduction in glomerular endothelial markers expression, which demonstrates the anti-angiogenic beneit [83]. This efect seems to be opposite when it applies to the diabetic heart failure model, as another HDACi sodium butyrate exerts improved cardiac functions and increased microvessel density within the diabetic myocardium [84]. Moreover, HDACi also modulates cardiac peroxisome proliferator-activated receptors (PPARs) and faty acid metabolism in diabetic cardiomyopathy [85].…”

Therapeutic Potential for Natural Product HDAC Inhibitors in Heart Failure

“…The previously described Valproic Acid is also a short-chain fatty acid HDACi [30]. Treatment with sodium butyrate or valproic acid inhibited cardiac hypertrophy and fibrosis and increased systolic function in pre-clinical rodent models of heart failure [46,51].…”