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Mitochondrial H2S Regulates BCAA Catabolism in Heart Failure
Circulation Research ( IF 20.1 ) Pub Date : 2022-06-14 , DOI: 10.1161/circresaha.121.319817
Zhen Li 1 , Huijing Xia 1 , Thomas E Sharp 1 , Kyle B LaPenna 1 , John W Elrod 2 , Kevin M Casin 3 , Ken Liu 4 , John W Calvert 3 , Vinh Q Chau 5 , Fadi N Salloum 5 , Shi Xu 6 , Ming Xian 6 , Noriyuki Nagahara 7 , Traci T Goodchild 1 , David J Lefer 1
Affiliation  

Background:Hydrogen sulfide (H2S) exerts mitochondria-specific actions that include the preservation of oxidative phosphorylation, biogenesis, and ATP synthesis, while inhibiting cell death. 3-MST (3-mercaptopyruvate sulfurtransferase) is a mitochondrial H2S-producing enzyme whose functions in the cardiovascular disease are not fully understood. In the current study, we investigated the effects of global 3-MST deficiency in the setting of pressure overload–induced heart failure.Methods:Human myocardial samples obtained from patients with heart failure undergoing cardiac surgeries were probed for 3-MST protein expression. 3-MST knockout mice and C57BL/6J wild-type mice were subjected to transverse aortic constriction to induce pressure overload heart failure with reduced ejection fraction. Cardiac structure and function, vascular reactivity, exercise performance, mitochondrial respiration, and ATP synthesis efficiency were assessed. In addition, untargeted metabolomics were utilized to identify key pathways altered by 3-MST deficiency.Results:Myocardial 3-MST was significantly reduced in patients with heart failure compared with nonfailing controls. 3-MST KO mice exhibited increased accumulation of branched-chain amino acids in the myocardium, which was associated with reduced mitochondrial respiration and ATP synthesis, exacerbated cardiac and vascular dysfunction, and worsened exercise performance following transverse aortic constriction. Restoring myocardial branched-chain amino acid catabolism with 3,6-dichlorobenzo1[b]thiophene-2-carboxylic acid (BT2) and administration of a potent H2S donor JK-1 ameliorates the detrimental effects of 3-MST deficiency in heart failure with reduced ejection fraction.Conclusions:Our data suggest that 3-MST derived mitochondrial H2S may play a regulatory role in branched-chain amino acid catabolism and mediate critical cardiovascular protection in heart failure.

中文翻译:

线粒体 H2S 调节心力衰竭中的 BCAA 分解代谢

背景:硫化氢 (H 2 S) 发挥线粒体特异性作用,包括保护氧化磷酸化、生物发生和 ATP 合成,同时抑制细胞死亡。3-MST(3-巯基丙酮酸硫转移酶)是一种线粒体H 2 S生成酶,其在心血管疾病中的功能尚不完全清楚。在当前的研究中,我们调查了整体 3-MST 缺乏对压力超负荷诱发心力衰竭的影响。方法:对从接受心脏手术的心力衰竭患者获取的人心肌样本进行了 3-MST 蛋白表达的检测。对 3-MST 基因敲除小鼠和 C57BL/6J 野生型小鼠进行横向主动脉缩窄,以诱导射血分数降低的压力超负荷心力衰竭。评估心脏结构和功能、血管反应性、运动表现、线粒体呼吸和 ATP 合成效率。此外,利用非靶向代谢组学来识别因 3-MST 缺乏而改变的关键通路。结果:与非心力衰竭对照者相比,心力衰竭患者的心肌 3-MST 显着降低。3-MST KO小鼠心肌中支链氨基酸的积累增加,这与线粒体呼吸和ATP合成减少、心脏和血管功能障碍加剧以及主动脉横缩后运动表现恶化有关。用 3,6-二氯苯并1[b]噻吩-2-羧酸 (BT2) 恢复心肌支链氨基酸分解代谢并给予有效的 H 2 S 供体 JK-1 可改善 3-MST 缺乏对心力衰竭的不利影响结论:我们的数据表明,3-MST 衍生的线粒体 H 2 S 可能在支链氨基酸分解代谢中发挥调节作用,并在心力衰竭中介导关键的心血管保护。
更新日期:2022-06-14
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