BCKDK Inhibitors Directly Antagonize Angiotensin II Type 1 Receptor and Induce Vasodilation Independently of BCAA Catabolism or BCKDK
- 1Duke University School of Medicine
Abstract
Branched-chain amino acids (BCAA) have been implicated in diabetes and heart failure, leading to ongoing clinical trials with inhibitors of BCKDK, a key regulator of BCAA catabolism. We have previously shown that these inhibitors promote vasodilation and lower blood pressure, well-known cardioprotective effects, but how this occurs remained unclear. We show here, using explanted vessels, in vivo hemodynamics and telemetry, and genetically modified mice, that the vasodilatory effect of BCKDK inhibitors is direct, rapid, independent of nitric oxide, independent of BCAA catabolism, and most strikingly, independent of BCKDK itself. Instead, we demonstrate, using structural and biochemical studies, that BCKDK inhibitors directly antagonize the angiotensin II type I receptor (AT1R) and consequent angiotensin-mediated vasoconstriction. These data demonstrate a strong off-target effect of BCKDK inhibitors, independent of BCAA or BCKDK, which may explain their cardioprotective effects but also questions if this protection would be additive to existing AT1R blockers.
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BibTeX
@misc{kawakami2026bckdk,
title = {{BCKDK Inhibitors Directly Antagonize Angiotensin II Type 1 Receptor and Induce Vasodilation Independently of BCAA Catabolism or BCKDK}},
author = {R. Kawakami and Y. Deleye and E. Akkaya and U. Pham and J. W. Jung and L. Lai and A. Chundi and S. Darbha and D. Murashige and R. Gaspar and W. He and G. Zhang and A. Kahsai and S. Rajagopal and P. J. White and Z. Arany and R. W. McGarrah},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.06.757051},
url = {https://www.biorxiv.org/content/10.64898/2026.10.06.757051v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - BCKDK Inhibitors Directly Antagonize Angiotensin II Type 1 Receptor and Induce Vasodilation Independently of BCAA Catabolism or BCKDK
AU - R. Kawakami
AU - Y. Deleye
AU - E. Akkaya
AU - U. Pham
AU - J. W. Jung
AU - L. Lai
AU - A. Chundi
AU - S. Darbha
AU - D. Murashige
AU - R. Gaspar
AU - W. He
AU - G. Zhang
AU - A. Kahsai
AU - S. Rajagopal
AU - P. J. White
AU - Z. Arany
AU - R. W. McGarrah
PY - 2026
DA - 2026/10/06
PB - bioRxiv
DO - 10.64898/2026.10.06.757051
UR - https://www.biorxiv.org/content/10.64898/2026.10.06.757051v1
AB - Branched-chain amino acids (BCAA) have been implicated in diabetes and heart failure, leading to ongoing clinical trials with inhibitors of BCKDK, a key regulator of BCAA catabolism. We have previously shown that these inhibitors promote vasodilation and lower blood pressure, well-known cardioprotective effects, but how this occurs remained unclear. We show here, using explanted vessels, in vivo hemodynamics and telemetry, and genetically modified mice, that the vasodilatory effect of BCKDK inhibitors is direct, rapid, independent of nitric oxide, independent of BCAA catabolism, and most strikingly, independent of BCKDK itself. Instead, we demonstrate, using structural and biochemical studies, that BCKDK inhibitors directly antagonize the angiotensin II type I receptor (AT1R) and consequent angiotensin-mediated vasoconstriction. These data demonstrate a strong off-target effect of BCKDK inhibitors, independent of BCAA or BCKDK, which may explain their cardioprotective effects but also questions if this protection would be additive to existing AT1R blockers.
ER -