Inhibition of HDAC6 Activity Alleviates Myocardial Ischemia/Reperfusion Injury in Diabetic Rats: Potential Role of Peroxiredoxin 1 Acetylation and Redox Regulation.

Yan Leng,Yang Wu,Shaoqing Lei,Zhongyuan Xia,Zhen Qiu,Bin Zhou,Kai Wang

doi:10.1155/2018/9494052

Abstract

Patients with diabetes are more vulnerable to myocardial ischemia/reperfusion (MI/R) injury, which is associated with excessive reactive oxygen species (ROS) generation and decreased antioxidant defense. Histone deacetylase 6 (HDAC6), a regulator of the antioxidant protein peroxiredoxin 1 (Prdx1), is associated with several pathological conditions in the cardiovascular system. This study investigated whether tubastatin A (TubA), a highly selective HDAC6 inhibitor, could confer a protective effect by modulating Prdx1 acetylation in a rat model of MI/R and an in vitro model of hypoxia/reoxygenation (H/R). Here, we found that diabetic hearts with excessive HDAC6 activity and decreased acetylated-Prdx1 levels were more vulnerable to MI/R injury. TubA treatment robustly improved cardiac function, reduced cardiac infarction, attenuated ROS generation, and increased acetylated-Prdx1 levels in diabetic MI/R rats. These results were further confirmed by an in vitro study using H9c2 cells. Furthermore, a study using Prdx1 acetyl-silencing mutants (K197R) showed that TubA only slightly attenuated H/R-induced cell death and ROS generation in K197R-transfected H9c2 cells exposed to high glucose (HG), but these differences were not statistically significant. Taken together, these findings suggest that HDAC6 inhibition reduces ROS generation and confers a protective effect against MI/R or H/R injury by modulating Prdx1 acetylation at K197.

Highlights

Diabetes mellitus (DM) is one of the most important risk factors for developing coronary heart disease [1]
We demonstrated that excessive reactive oxygen species (ROS) accumulation in diabetic hearts is accompanied by increased Histone deacetylase 6 (HDAC6) activity and decreased peroxiredoxin 1 (Prdx1) acetylation
The protective effect of HDAC6 inhibition was partly abrogated in Prdx1 nonacetylated mimic mutant (K197R) cardiomyocytes, suggesting that HDAC6 alleviates H/R-induced O2− and H2O2 accumulation by modulating Prdx1 acetylation at K197

Summary

Introduction

Diabetes mellitus (DM) is one of the most important risk factors for developing coronary heart disease [1]. The mortality rate is significantly higher among patients with DM than among those without DM who present with acute myocardial infarction (AMI) [2]. Intracellular hyperglycemiainduced ROS production and decreased antioxidant defenses may render diabetic hearts more vulnerable to MI/R injury [6]. Researchers have found that ROS scavengers can reduce the MI/R-induced infarct size, which suggests that the response to MI/R can be manipulated by eliminating ROS to alleviate injury [7,8,9]. The cellular mechanisms controlling ROS production and scavenging are not fully understood

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