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Catabolic Defect of Branched-Chain Amino Acids Promotes Heart Failure.

Publication ,  Journal Article
Sun, H; Olson, KC; Gao, C; Prosdocimo, DA; Zhou, M; Wang, Z; Jeyaraj, D; Youn, J-Y; Ren, S; Liu, Y; Rau, CD; Shah, S; Ilkayeva, O; Gui, W-J ...
Published in: Circulation
May 24, 2016

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.

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Published In

Circulation

DOI

EISSN

1524-4539

Publication Date

May 24, 2016

Volume

133

Issue

21

Start / End Page

2038 / 2049

Location

United States

Related Subject Headings

  • Transcriptome
  • Mice, Knockout
  • Mice
  • Metabolomics
  • Metabolism
  • Male
  • Humans
  • Heart Failure
  • Cardiovascular System & Hematology
  • Animals
 

Citation

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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
Sun, Haipeng, Kristine C. Olson, Chen Gao, Domenick A. Prosdocimo, Meiyi Zhou, Zhihua Wang, Darwin Jeyaraj, et al. “Catabolic Defect of Branched-Chain Amino Acids Promotes Heart Failure.Circulation 133, no. 21 (May 24, 2016): 2038–49. 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):2038–49.
Sun, Haipeng, et al. “Catabolic Defect of Branched-Chain Amino Acids Promotes Heart Failure.Circulation, vol. 133, no. 21, May 2016, pp. 2038–49. Pubmed, doi:10.1161/CIRCULATIONAHA.115.020226.
Sun H, Olson KC, Gao C, Prosdocimo DA, Zhou M, Wang Z, Jeyaraj D, Youn J-Y, Ren S, Liu Y, Rau CD, Shah S, Ilkayeva O, Gui W-J, William NS, Wynn RM, Newgard CB, Cai H, Xiao X, Chuang DT, Schulze PC, Lynch C, Jain MK, Wang Y. Catabolic Defect of Branched-Chain Amino Acids Promotes Heart Failure. Circulation. 2016 May 24;133(21):2038–2049.

Published In

Circulation

DOI

EISSN

1524-4539

Publication Date

May 24, 2016

Volume

133

Issue

21

Start / End Page

2038 / 2049

Location

United States

Related Subject Headings

  • Transcriptome
  • Mice, Knockout
  • Mice
  • Metabolomics
  • Metabolism
  • Male
  • Humans
  • Heart Failure
  • Cardiovascular System & Hematology
  • Animals