BCKDK Inhibitors Directly Antagonize Angiotensin II Type 1 Receptor and Induce Vasodilation Independently of BCAA Catabolism or BCKDK
Kawakami, R.; Deleye, Y.; Akkaya, E.; Pham, U.; Jung, J. W.; Lai, L.; Chundi, A.; Darbha, S.; Murashige, D.; Gaspar, R.; He, W.; Zhang, G.; Kahsai, A.; Rajagopal, S.; White, P. J.; Arany, Z.; McGarrah, R. W.
Show 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.
Matching journals
The top 8 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Glycaemic variability underlies myocyte dysfunction and myocardial injury risk in diabetes 95%
- Vascular smooth muscle cell atherosclerosis trajectories characterized at single cell resolution identify causal transcriptomic and epigenomic mechanisms of disease risk 93%
- IL-27 receptor signaling regulated stress myelopoiesis drives Abdominal Aortic Aneurysm development 93%
Similar papers in this journal
Similar papers in this journal
- Golgi localized β1-adrenergic receptors stimulate Golgi PI4P hydrolysis by PLCε to regulate cardiac hypertrophy 92%
- Endothelial Pannexin 1-TRPV4 channel signaling lowers pulmonary arterial pressure 92%
- Single-Cell RNA-seq of Heart Reveals Intercellular Communication Drivers of Myocardial Fibrosis in Diabetic Mice 92%
Similar papers in this journal
- Immunomodulation by AZD1656 reverses cardiac dysfunction, metabolic remodelling and reduces infarct size in type 2 diabetic cardiomyopathy 95%
- Targeted glycophagy ATG8 therapy reverses diabetic heart disease in mice and in human engineered cardiac tissues 93%
- Integrative proteomic analyses across common cardiac diseases yield new mechanistic insights and enhanced prediction 92%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.