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Therapeutic Effect of Targeting Branched-Chain Amino Acid Catabolic Flux in Pressure-Overload Induced Heart Failure.

Publication ,  Journal Article
Chen, M; Gao, C; Yu, J; Ren, S; Wang, M; Wynn, RM; Chuang, DT; Wang, Y; Sun, H
Published in: J Am Heart Assoc
June 4, 2019

Background Branched-chain amino acid (BCAA) catabolic defect is an emerging metabolic hallmark in failing hearts in human and animal models. The therapeutic impact of targeting BCAA catabolic flux under pathological conditions remains understudied. Methods and Results BT2 (3,6-dichlorobenzo[b]thiophene-2-carboxylic acid), a small-molecule inhibitor of branched-chain ketoacid dehydrogenase kinase, was used to enhance BCAA catabolism. After 2 weeks of transaortic constriction, mice with significant cardiac dysfunctions were treated with vehicle or BT2. Serial echocardiograms showed continuing pathological deterioration in left ventricle of the vehicle-treated mice, whereas the BT2-treated mice showed significantly preserved cardiac function and structure. Moreover, BT2 treatment improved systolic contractility and diastolic mechanics. These therapeutic benefits appeared to be independent of impacts on left ventricle hypertrophy but associated with increased gene expression involved in fatty acid utilization. The BT2 administration showed no signs of apparent toxicity. Conclusions Our data provide the first proof-of-concept evidence for the therapeutic efficacy of restoring BCAA catabolic flux in hearts with preexisting dysfunctions. The BCAA catabolic pathway represents a novel and potentially efficacious target for treatment of heart failure.

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Published In

J Am Heart Assoc

DOI

EISSN

2047-9980

Publication Date

June 4, 2019

Volume

8

Issue

11

Start / End Page

e011625

Location

England

Related Subject Headings

  • Ventricular Function, Left
  • Recovery of Function
  • Rats, Sprague-Dawley
  • Protein Kinase Inhibitors
  • Phosphorylation
  • Myocardium
  • Myocardial Contraction
  • Mice, Inbred C57BL
  • Metabolism
  • Male
 

Citation

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Chen, M., Gao, C., Yu, J., Ren, S., Wang, M., Wynn, R. M., … Sun, H. (2019). Therapeutic Effect of Targeting Branched-Chain Amino Acid Catabolic Flux in Pressure-Overload Induced Heart Failure. J Am Heart Assoc, 8(11), e011625. https://doi.org/10.1161/JAHA.118.011625
Chen, Mengping, Chen Gao, Jiayu Yu, Shuxun Ren, Menglong Wang, R Max Wynn, David T. Chuang, Yibin Wang, and Haipeng Sun. “Therapeutic Effect of Targeting Branched-Chain Amino Acid Catabolic Flux in Pressure-Overload Induced Heart Failure.J Am Heart Assoc 8, no. 11 (June 4, 2019): e011625. https://doi.org/10.1161/JAHA.118.011625.
Chen M, Gao C, Yu J, Ren S, Wang M, Wynn RM, et al. Therapeutic Effect of Targeting Branched-Chain Amino Acid Catabolic Flux in Pressure-Overload Induced Heart Failure. J Am Heart Assoc. 2019 Jun 4;8(11):e011625.
Chen, Mengping, et al. “Therapeutic Effect of Targeting Branched-Chain Amino Acid Catabolic Flux in Pressure-Overload Induced Heart Failure.J Am Heart Assoc, vol. 8, no. 11, June 2019, p. e011625. Pubmed, doi:10.1161/JAHA.118.011625.
Chen M, Gao C, Yu J, Ren S, Wang M, Wynn RM, Chuang DT, Wang Y, Sun H. Therapeutic Effect of Targeting Branched-Chain Amino Acid Catabolic Flux in Pressure-Overload Induced Heart Failure. J Am Heart Assoc. 2019 Jun 4;8(11):e011625.
Journal cover image

Published In

J Am Heart Assoc

DOI

EISSN

2047-9980

Publication Date

June 4, 2019

Volume

8

Issue

11

Start / End Page

e011625

Location

England

Related Subject Headings

  • Ventricular Function, Left
  • Recovery of Function
  • Rats, Sprague-Dawley
  • Protein Kinase Inhibitors
  • Phosphorylation
  • Myocardium
  • Myocardial Contraction
  • Mice, Inbred C57BL
  • Metabolism
  • Male