Catabolic Defect of Branched-Chain Amino Acids Promotes Heart Failure.
Catabolic Defect of Branched-Chain Amino Acids Promotes Heart Failure.
复制标题
支链氨基酸的分解代谢缺陷促进心力衰竭
DOI：
10.1161/circulationaha.115.020226
复制
发表时间：
2016-05-24
期刊：
影响因子：
37.8
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Sun H;Olson KC;Gao C;Prosdocimo DA;Zhou M;Wang Z;Jeyaraj D;Youn JY;Ren S;Liu Y;Rau CD;Shah S;Ilkayeva O;Gui WJ;William NS;Wynn RM;Newgard CB;Cai H;Xiao X;Chuang DT;Schulze PC;Lynch C;Jain MK;Wang Y
尽管代谢重编程在心力衰竭的发病机制中至关重要，但迄今为止的研究主要集中在脂肪酸和葡萄糖代谢上。氨基酸代谢调节在该疾病中的作用仍有待研究。对压力超负荷引起的小鼠心脏衰竭进行转录组学和代谢组学分析。支链氨基酸 (BCAA) 分解代谢基因表达的抑制以及伴随的支链 α-酮酸 (BCKA) 的组织积累被确定为小鼠衰竭心脏代谢重编程的重要特征，并经验证在人类心肌病心脏中也存在这种现象。分子和遗传学证据表明转录因子 KLF15 是心脏 BCAA 分解代谢调节的关键上游调节因子。使用遗传小鼠模型的研究表明，BCAA 分解代谢缺陷会促进心力衰竭，而心力衰竭与机械超负荷引起的氧化应激和代谢紊乱有关。从机制上讲，升高的 BCKA 直接抑制呼吸并诱导分离线粒体中超氧化物的产生。最后，支链α-酮酸脱氢酶活性的药理学增强显着减弱了压力超负荷后的心脏功能障碍。 BCAA 分解代谢缺陷是 KLF15 介导的转录重编程导致的心脏衰竭的代谢标志。 BCAA 分解代谢缺陷对心力衰竭产生了以前未被认识到的重大影响。
Although metabolic reprogramming is critical in the pathogenesis of heart failure, studies to date have focused principally on fatty acid and glucose metabolism. Contribution of amino acid metabolic regulation in the disease remains understudied. Transcriptomic and metabolomic analyses were performed in mouse failing heart induced by pressure-overload. Suppression of branched-chain amino acids (BCAAs) catabolic gene expression along with concomitant tissue accumulation of branched-chain α-keto acids (BCKAs) was identified as a significant signature of metabolic reprogramming in mouse failing hearts, and validated to be shared in human cardiomyopathy hearts. Molecular and genetic evidence identified the transcription factor KLF15 as a key upstream regulator of the BCAA catabolic regulation in the heart. Studies using a genetic mouse model revealed that BCAA catabolic defect promoted heart failure associated with induced oxidative stress and metabolic disturbance in response to mechanical overload. Mechanistically, elevated BCKA directly suppressed respiration and induced superoxide production in isolated mitochondria. Finally, pharmacological enhancement of branched-chain α-keto acid dehydrogenase activity significantly blunted cardiac dysfunction following pressure-overload. BCAA catabolic defect is a metabolic hallmark of failing heart resulted from KLF15 mediated transcriptional reprogramming. BCAA catabolic defect imposes a previously unappreciated significant contribution to heart failure.