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

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.

Metabolism and Chronic Inflammation: The Links Between Chronic Heart Failure and Comorbidities

“…BCAA accumulation could result in insulin resistance by activating the mTOR pathway ( 34 , 35 ), and accumulated BCKAs would increase reactive oxygen species (ROS) ( 36 ). Furthermore, BCAA is reported to be a potential therapeutic target for HF ( 37 ). BCAAs are not a major source of cardiac energy (below 5%) ( 28 ).…”

Inhibition of the canonical Wnt signaling pathway by a β-catenin/CBP inhibitor prevents heart failure by ameliorating cardiac hypertrophy and fibrosis

“…Metabolic profiling demonstrated that amino acids including leucine, isoleucine, valine, lysine, phenylalanine, serine, tryptophan, and tyrosine were increased in TAC mice but significantly decreased in ICG001-treated TAC mice. Reducing the cardiac intratissue concentration of BCAA in TAC mice by increasing the BCAA catabolism preserves cardiac function and structure 53 ; thus, stimulation of BCAA catabolism which correlated with PPAR-α upregulation may be one of the mechanisms that ICG001 protects the heart from HF. Furthermore, although ICG001 did not influence G1P and G6P, it did influence G3P, a metabolite connecting glycolysis, lipogenesis, and oxidative stress 54 , after TAC.…”

Is branched-chain amino acid nutritional supplementation beneficial or detrimental in heart failure?

“…By contrast, some hopeful hints about the BCAA metabolic pathway in heart failure therapy might exist. In BCKDK regulation, 3,6-dichlorobenzo[b]thiophene-2-carboxylic acid (BT2), a small-molecule BCKDK inhibitor, blocks BCKD phosphorylation, leading to increased BCAA catabolism[ 34 ]. Moreover, BT2 might alleviate oxidative stress by reducing BCKA or mTOR complex 1 activity by lowering BCAA concentrations, thereby improving cardiac function[ 35 ].…”

“…Moreover, BT2 might alleviate oxidative stress by reducing BCKA or mTOR complex 1 activity by lowering BCAA concentrations, thereby improving cardiac function[ 35 ]. A study of BT2 administration to mice suggested that BT2 treatment improved cardiac function and led to remodeling without apparent toxicity[ 34 ].…”