支链氨基酸的分解代谢缺陷促进心力衰竭。
Catabolic Defect of Branched-Chain Amino Acids Promotes Heart Failure.
作者信息
Sun Haipeng, Olson Kristine C, Gao Chen, Prosdocimo Domenick A, Zhou Meiyi, Wang Zhihua, Jeyaraj Darwin, Youn Ji-Youn, Ren Shuxun, Liu Yunxia, Rau Christoph D, Shah Svati, Ilkayeva Olga, Gui Wen-Jun, William Noelle S, Wynn R Max, Newgard Christopher B, Cai Hua, Xiao Xinshu, Chuang David T, Schulze Paul Christian, Lynch Christopher, Jain Mukesh K, Wang Yibin
机构信息
From Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China (H.S., M.Z., Y.L., Y.W.); Division of Molecular Medicine, Departments of Anesthesiology, Medicine, and Physiology, Molecular Biology Institute, Cardiovascular Research Laboratories, David Geffen School of Medicine at University of California, Los Angeles (H.S., C.G., Z.W., J.-Y.Y., S.R., C.D.R., H.C., X.X., Y.W.); Department of Cellular and Molecular Physiology, Penn State University College of Medicine, Hershey, PA (K.C.O., C.L.); Case Cardiovascular Research Institute, Harrington Heart and Vascular Institute, Department of Medicine, Case Western Reserve University, Cleveland, OH (D.A.P., D.J., M.K.J.); Division of Cardiology, Department of Medicine (S.S.) and Sarah W. Stedman Nutrition and Metabolism Center, Departments of Medicine and Pharmacology and Cancer Biology (O.I., C.B.N.), and Duke University School of Medicine, Durham, NC; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas (W.-J.G., N.S.W., R.M.W., D.T.C.); and Division of Cardiology, Department of Medicine, Columbia University Medical Center, New York, NY (P.C.S.). Dr Schulze is now at the Department of Internal Medicine, Division of Cardiology, Angiology, Pneumology and Intensive Medical Care, Friedrich-Schiller-University, Jena, Germany.
出版信息
Circulation. 2016 May 24;133(21):2038-49. doi: 10.1161/CIRCULATIONAHA.115.020226. Epub 2016 Apr 8.
BACKGROUND
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.
METHODS AND RESULTS
Transcriptomic and metabolomic analyses were performed in mouse failing heart induced by pressure overload. Suppression of branched-chain amino acid (BCAA) catabolic gene expression along with concomitant tissue accumulation of branched-chain α-keto acids 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 Krüppel-like factor 15 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 branched-chain α-keto acids 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 after pressure overload.
CONCLUSIONS
BCAA catabolic defect is a metabolic hallmark of failing heart resulting from Krüppel-like factor 15-mediated transcriptional reprogramming. BCAA catabolic defect imposes a previously unappreciated significant contribution to heart failure.
背景
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未得到充分研究。
方法和结果
对压力超负荷诱导的小鼠衰竭心脏进行了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支链α-酮酸在组织中的累积被确定为小鼠衰竭心脏代谢重编程的一个重要特征，并在人类心肌病心脏中得到验证。分子和遗传学证据确定转录因子Krüppel样因子15是心脏中BCAA分解代谢调节的关键上游调节因子。使用基因小鼠模型的研究表明，BCAA分解代谢缺陷促进了心力衰竭，这与机械超负荷引起的氧化应激和代谢紊乱有关。机制上，升高的支链α-酮酸直接抑制呼吸并在分离的线粒体中诱导超氧化物产生。最后，支链α-酮酸脱氢酶活性的药理学增强显著减轻了压力超负荷后的心脏功能障碍。
结论
BCAA分解代谢缺陷是由Krüppel样因子15介导的转录重编程导致的衰竭心脏的代谢标志。BCAA分解代谢缺陷对心力衰竭有此前未被认识到的重大影响。
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