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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Chen, M; Gao, C; Yu, J; Ren, S; Wang, M; Wynn, RM; Chuang, DT; Wang, Y; Sun, H

Published Date

  • June 4, 2019

Published In

Volume / Issue

  • 8 / 11

Start / End Page

  • e011625 -

PubMed ID

  • 31433721

Pubmed Central ID

  • PMC6585363

Electronic International Standard Serial Number (EISSN)

  • 2047-9980

Digital Object Identifier (DOI)

  • 10.1161/JAHA.118.011625

Language

  • eng

Conference Location

  • England