부산대학교 도서관

Introduction:Hydrogen sulfide (H2S) exerts mitochondria-specific actions that include the preservation of mitochondrial respiration, biogenesis, and ATP synthesis, while inhibiting apoptosis. 3-mercaptopyruvate sulfurtransferase (3-MST) is a mitochondrial H2S producing enzyme whose functions in cardiovascular physiology and pathology are yet to be fully elucidated. In the present study, we investigated the effects of global 3-MST deficiency in the setting of pressure overload-induced heart failure.Methods:3-MST knockout mice and C57BL/6J wild-type mice were subjected to transverse aortic constriction (TAC) to induce pressure-overload HFrEF. Cardiac structure and function, vascular reactivity, exercise performance, mitochondrial function and ATP synthesis efficiency were assessed. Additionally, unbiased metabolomic approaches were utilized to identify key pathways altered by 3-MST deficiency.Results:3-MST KO mice exhibited increased accumulation of branched-chain amino acids (BCAAs) in the myocardium, resulting in reduced mitochondrial respiration and ATP synthesis, exacerbated cardiac and vascular dysfunction, and worsened exercise intolerance in HFrEF. Promoting BCAAs catabolism through 3,6-dichlorobenzo1[b]thiophene-2-carboxylaic acid (BT2) treatment mitigated the detrimental effects of 3-MST deficiency and ameliorates the severity of HFrEF.Conclusions:Our data demonstrate that deficiency of 3-MST significantly inhibits BCAAs catabolism and impairs mitochondrial respiration and ATP synthesis efficiency, resulting in worsened HFrEF. These data suggest that 3-MST is critical in the protective response to cardiovascular diseases such as heart failure. Future studies are underway to define the mechanism by which 3-MST regulates BCAAs catabolism.