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

Mengping Chen, Chen Gao, Jiayu Yu, Shuxun Ren, Menglong Wang, Richard M Wynn, David T Chuang, Yibin Wang, Haipeng Sun

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article numbere011625
JournalJournal of the American Heart Association
Volume8
Issue number11
DOIs
StatePublished - Jun 4 2019

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Branched Chain Amino Acids
Therapeutic Uses
Heart Failure
Pressure
Heart Ventricles
3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)
Mechanics
Treatment Failure
Constriction
Hypertrophy
Phosphotransferases
Fatty Acids
Therapeutics
Animal Models
thiophene-2-carboxylate
Gene Expression

Keywords

  • amino acids
  • heart failure
  • hypertrophy/remodeling
  • metabolism
  • therapy

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Therapeutic Effect of Targeting Branched-Chain Amino Acid Catabolic Flux in Pressure-Overload Induced Heart Failure. / Chen, Mengping; Gao, Chen; Yu, Jiayu; Ren, Shuxun; Wang, Menglong; Wynn, Richard M; Chuang, David T; Wang, Yibin; Sun, Haipeng.

In: Journal of the American Heart Association, Vol. 8, No. 11, e011625, 04.06.2019.

Research output: Contribution to journalArticle

Chen, Mengping ; Gao, Chen ; Yu, Jiayu ; Ren, Shuxun ; Wang, Menglong ; Wynn, Richard M ; Chuang, David T ; Wang, Yibin ; Sun, Haipeng. / Therapeutic Effect of Targeting Branched-Chain Amino Acid Catabolic Flux in Pressure-Overload Induced Heart Failure. In: Journal of the American Heart Association. 2019 ; Vol. 8, No. 11.
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