Exogenous H2S facilitating ubiquitin aggregates clearance via autophagy attenuates type 2 diabetes-induced cardiomyopathy

Abstract

Diabetic cardiomyopathy (DCM) is a serious complication of diabetes. Hydrogen sulphide (H2S), 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 H2S 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 H2S 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 H2S promoted ubiquitin aggregate clearance via autophagy, which might exert its antioxidative effect in db/db mouse myocardia. Moreover, exogenous H2S 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 H2S in the context of T2DCM.

Exogenous H2S Induces Hrd1 S-sulfhydration and Prevents CD36 Translocation via VAMP3 Ubiquitylation in Diabetic Hearts

“…Hydrogen sulfide (H2S), the third identified gasotransmitter after nitric oxide and carbon monoxide, is involved in a wide range of physiological and pathological processes. Our previous study suggested that H2S inhibits the ubiquitylation of superoxide dismutase (SOD) to promote the initiation of autophagy in diabetic cardiomyopathy [14]. Ji et al demonstrated that H2S regulates Krüppel-like factor 5 (KLF5) transcriptional activity via specific protein S-sulfhydration to prevent myocardial hypertrophy [15].…”

Hydrogen sulfide regulates muscle RING finger‐1 protein S‐sulfhydration at Cys44 to prevent cardiac structural damage in diabetic cardiomyopathy

“…Our previous study showed that exogenous H 2 S could facilitate the clearance of ubiquitin aggregates by promoting autophagy, which contributed to its antioxidative effects in DCM (J. Wu et al, 2017). Nevertheless, the pathogenesis of DCM is complex, and the precise mechanism by which H 2 S may protect against DCM has not been thoroughly elucidated (Popov, 2013).…”

Hydrogen Sulfide Regulating Myocardial Structure and Function by Targeting Cardiomyocyte Autophagy

“…[ 43 44 ] However, other research teams reported that H 2 S could protect myocardiocytes by promoting autophagy in a type 2 diabetes model. [ 45 46 ] Thus, how H 2 S exerts its protective effects on cardiomyocytes through autophagy merits further studies. We reviewed various studies investigating the regulation of autophagy by H 2 S in cardiovascular diseases to shed new light on the mechanisms for the cardioprotective role of H 2 S.…”