The Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid (SAHA) Restores Cardiomyocyte Contractility in a Rat Model of Early Diabetes

Abstract

In early diabetes, hyperglycemia and the associated metabolic dysregulation promote early changes in the functional properties of cardiomyocytes, progressively leading to the appearance of the diabetic cardiomyopathy phenotype. Recently, the interplay between histone acetyltransferases (HAT) and histone deacetylases (HDAC) has emerged as a crucial factor in the development of cardiac disorders. The present study evaluates whether HDAC inhibition can prevent the development of cardiomyocyte contractile dysfunction induced by a short period of hyperglycemia, with focus on the potential underlying mechanisms. Cell contractility and calcium dynamics were measured in unloaded ventricular myocytes isolated from the heart of control and diabetic rats. Cardiomyocytes were either untreated or exposed to the pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) for 90 min. Then, a fraction of each group of cells was used to evaluate the expression levels of proteins involved in the excitation–contraction coupling, and the cardiomyocyte metabolic activity, ATP content, and reactive oxygen species levels. SAHA treatment was able to counteract the initial functional derangement in cardiomyocytes by reducing cell oxidative damage. These findings suggest that early HDAC inhibition could be a promising adjuvant approach for preventing diabetes-induced cardiomyocyte oxidative damage, which triggers the pro-inflammatory signal cascade, mitochondrial damage, and ventricular dysfunction.

Beta-Hydroxybutyrate, Friend or Foe for Stressed Hearts

“…It has been reported that HDACs activity is elevated in models of heart failure, diabetic heart, and myocardial I/R injury (Granger et al, 2008;Nural-Guvener et al, 2014;Evans and Ferguson, 2018;Bocchi et al, 2019). Class I and II HDAC inhibitors represent a group of small molecule epigenetic modifiers that have demonstrated efficacy in animal models of heart failure over the last decade (Evans and Ferguson, 2018).…”

“…HDAC inhibition has also been used as a therapeutic strategy for cardiac I/R injury (Xie et al, 2019). Emerging evidence also suggests that inhibition of HDACs protects the heart against myocardial injury and stimulates endogenous angiomyogenesis even in the diabetic heart (Bocchi et al, 2019). Thus, inhibition of HDACs using small molecules has been thought to be a promising approach to treat many pathological disorders.…”

The Emerging Role of HDACs: Pathology and Therapeutic Targets in Diabetes Mellitus

“…Additionally, MPT0E014 can improve cardiac function by modulating myocardial autophagy and insulin signalling in T2D rats [232,233]. HDACs inhibition by SAHA is regarded to counteract the oxidative stress and functional changes in cardiomyocytes during the early stage of DM [234]. RGFP966, a specific inhibitor of HDAC3, was found to abrogate the initiation of diabetic cardiomyopathy by endorsing dual-specificity phosphatase 5 (DUSP5) activation by acetylating histone H3 on the DUSP5 primer region leading to an extracellular-signal-regulated kinase (Erk)1/2 activation [150].…”

The role of SIRT2 in vascular‐related and heart‐related diseases: A review

“…At present, there are very few direct studies on the relationship between SIRT2 and diabetic cardiomyopathy. It is interesting that other literatures indicate the use of HDAC inhibitors, such as sodium butyrate, 47 MPT0E014, 48 RGFP966 (a kind of selective HDAC3 inhibitor), 49 suberoylanilide hydroxamic acid (SAHA), 50 can well control the occurrence and development of diabetic cardiomyopathy. However, because the sirtuins family belongs to the third category of HDACs, the effects of these two conditions for diabetic cardiomyopathy are completely opposite.…”