Journal
CELL METABOLISM
Volume 34, Issue 11, Pages 1749-+Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2022.09.008
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Funding
- University of Pennsylvania DRC Rodent Metabolic Phenotyping Core and Metabolomics Core [NIH P30-DK19525, S10-OD025098]
- NHLBI [F30 HL142186-01A1, T32 HL 7954-20, HL152446]
- Blavatnik Family Foundation
- NIH [5T32CA257957, F32HL151146, AG162140]
- Institute for Translational Medicine and Therapeutics of the Perelman School of Medicine
- NIH/NHLBI [T32HL007843]
- Measey Foundation
- Leducq [19CV03]
- ADA [1-18-PDF-153]
- Edward Mallinckrodt Jr. Foundation
- Department of Defense [W81XWH18-1-0503]
- Pfizer
- [R01 HL149891]
- [R01 HL105993]
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Contrary to previous assumptions, activation of branched-chain amino acid (BCAA) oxidation actually increases in heart failure (HF) patients. Activation of cardiac BCAA oxidation does not protect from HF, but systemic activation does. Lowering plasma and cardiac BCAAs also does not confer significant protection. Surprisingly, BCAA catabolism leads to lower blood pressure independently of nitric oxide, suggesting a potential mechanism for cardioprotection in HF.
Pharmacologic activation of branched-chain amino acid (BCAA) catabolism is protective in models of heart failure (HF). How protection occurs remains unclear, although a causative block in cardiac BCAA oxidation is widely assumed. Here, we use in vivo isotope infusions to show that cardiac BCAA oxidation in fact increases, rather than decreases, in HF. Moreover, cardiac-specific activation of BCAA oxidation does not protect from HF even though systemic activation does. Lowering plasma and cardiac BCAAs also fails to confer significant protection, suggesting alternative mechanisms of protection. Surprisingly, activation of BCAA catabolism lowers blood pressure (BP), a known cardioprotective mechanism. BP lowering occurred independently of nitric oxide and reflected vascular resistance to adrenergic constriction. Mendelian randomization studies revealed that elevated plasma BCAAs portend higher BP in humans. Together, these data indicate that BCAA oxidation lowers vascular resistance, perhaps in part explaining cardioprotection in HF that is not mediated directly in cardiomyocytes.
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