Extra-cardiac BCAA catabolism lowers blood pressure and protects from heart failure

Danielle Murashige, Jae Woo Jung, Michael D. Neinast, Michael G. Levin, Qingwei Chu, Jonathan P. Lambert, Joanne F. Garbincius, Boa Kim, Atsushi Hoshino, Ingrid Marti-Pamies, Kendra S. McDaid, Swapnil V. Shewale, Emily Flam, Steven Yang, Emilia Roberts, Li Li, Michael P. Morley, Kenneth C. Bedi, Matthew C. Hyman, David S. FrankelKenneth B. Margulies, Richard K. Assoian, John W. Elrod, Cholsoon Jang, Joshua D. Rabinowitz, Zoltan Arany

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1749-1764.e7
JournalCell Metabolism
Volume34
Issue number11
DOIs
StatePublished - Nov 1 2022
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Physiology
  • Cell Biology

Keywords

  • BCAA
  • Mendelian randomization
  • blood pressure
  • branched-chain amino acid
  • cardiac metabolism
  • cardiovascular metabolism
  • heart failure
  • hypertension
  • metabolomics

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