Catabolic defect of branched-chain amino acids promotes heart failure

Haipeng Sun, Kristine C. Olson, Chen Gao, Domenick A. Prosdocimo, Meiyi Zhou, Zhihua Wang, Darwin Jeyaraj, Ji Youn Youn, Shuxun Ren, Yunxia Liu, Christoph D. Rau, Svati Shah, Olga Ilkayeva, Wen Jun Gui, Noelle S. William, R. Max Wynn, Christopher B. Newgard, Hua Cai, Xinshu Xiao, David T. Chuang & 4 others Paul Christian Schulze, Christopher Lynch, Mukesh K. Jain, Yibin Wang

Research output: Contribution to journalArticle

87 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2038-2049
Number of pages12
JournalCirculation
Volume133
Issue number21
DOIs
StatePublished - May 24 2016

Fingerprint

Branched Chain Amino Acids
Heart Failure
Keto Acids
3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)
Pressure
Metabolomics
Genetic Models
Cardiomyopathies
Superoxides
Molecular Biology
Mitochondria
Respiration
Oxidative Stress
Transcription Factors
Fatty Acids
Pharmacology
Gene Expression
Amino Acids
Glucose

Keywords

  • amino acids
  • heart failure
  • metabolism
  • oxidant stress
  • pathogenesis
  • remodeling

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Sun, H., Olson, K. C., Gao, C., Prosdocimo, D. A., Zhou, M., Wang, Z., ... Wang, Y. (2016). Catabolic defect of branched-chain amino acids promotes heart failure. Circulation, 133(21), 2038-2049. https://doi.org/10.1161/CIRCULATIONAHA.115.020226

Catabolic defect of branched-chain amino acids promotes heart failure. / 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.

In: Circulation, Vol. 133, No. 21, 24.05.2016, p. 2038-2049.

Research output: Contribution to journalArticle

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 2016, 'Catabolic defect of branched-chain amino acids promotes heart failure', Circulation, vol. 133, no. 21, pp. 2038-2049. https://doi.org/10.1161/CIRCULATIONAHA.115.020226
Sun H, Olson KC, Gao C, Prosdocimo DA, Zhou M, Wang Z et al. Catabolic defect of branched-chain amino acids promotes heart failure. Circulation. 2016 May 24;133(21):2038-2049. https://doi.org/10.1161/CIRCULATIONAHA.115.020226
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. / Catabolic defect of branched-chain amino acids promotes heart failure. In: Circulation. 2016 ; Vol. 133, No. 21. pp. 2038-2049.
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AU - Newgard, Christopher B.

AU - Cai, Hua

AU - Xiao, Xinshu

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