Exogenous H(2)S facilitating ubiquitin aggregates clearance via autophagy attenuates type 2 diabetes-induced cardiomyopathy

Diabetic cardiomyopathy (DCM) is a serious complication of diabetes. Hydrogen sulphide (H(2)S), a newly found gaseous signalling molecule, has an important role in many regulatory functions. The purpose of this study is to investigate the effects of exogenous H(2)S on autophagy and its possible mechanism in DCM induced by type II diabetes (T2DCM). In this study, we found that sodium hydrosulphide (NaHS) attenuated the augment in left ventricular (LV) mass and increased LV volume, decreased reactive oxygen species (ROS) production and ameliorated H(2)S production in the hearts of db/db mice. NaHS facilitated autophagosome content degradation, reduced the expression of P62 (a known substrate of autophagy) and increased the expression of microtubule-associated protein 1 light chain 3 II. It also increased the expression of autophagy-related protein 7 (ATG7) and Beclin1 in db/db mouse hearts. NaHS increased the expression of Kelch-like ECH-associated protein 1 (Keap-1) and reduced the ubiquitylation level in the hearts of db/db mice. 1,4-Dithiothreitol, an inhibitor of disulphide bonds, increased the ubiquitylation level of Keap-1, suppressed the expression of Keap-1 and abolished the effects of NaHS on ubiquitin aggregate clearance and ROS production in H9C2 cells treated with high glucose and palmitate. Overall, we concluded that exogenous H(2)S promoted ubiquitin aggregate clearance via autophagy, which might exert its antioxidative effect in db/db mouse myocardia. Moreover, exogenous H(2)S increased Keap-1 expression by suppressing its ubiquitylation, which might have an important role in ubiquitin aggregate clearance via autophagy. Our findings provide new insight into the mechanisms responsible for the antioxidative effects of H(2)S in the context of T2DCM.