Haipeng Sun1, Kristine C Olson1, Chen Gao1, Domenick A Prosdocimo1, Meiyi Zhou1, Zhihua Wang1, Darwin Jeyaraj1, Ji-Youn Youn1, Shuxun Ren1, Yunxia Liu1, Christoph D Rau1, Svati Shah1, Olga Ilkayeva1, Wen-Jun Gui1, Noelle S William1, R Max Wynn1, Christopher B Newgard1, Hua Cai1, Xinshu Xiao1, David T Chuang1, Paul Christian Schulze1, Christopher Lynch1, Mukesh K Jain1, Yibin Wang2. 1. 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. 2. 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. yibinwang@mednet.ucla.edu mxj84@case.edu.
Abstract
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.
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 humancardiomyopathy 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.
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