Skip to main content
eScholarship
Open Access Publications from the University of California

UCLA

UCLA Previously Published Works bannerUCLA

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

  • Author(s): Chen, Mengping
  • Gao, Chen
  • Yu, Jiayu
  • Ren, Shuxun
  • Wang, Menglong
  • Wynn, R Max
  • Chuang, David T
  • Wang, Yibin
  • Sun, Haipeng
  • et al.
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.

Many UC-authored scholarly publications are freely available on this site because of the UC's open access policies. Let us know how this access is important for you.

Main Content
Current View