Branched-chain α-ketoacids aerobically activate HIF1α signalling in vascular cells

Hypoxia-inducible factor 1α (HIF1α) is a master regulator of biological processes in hypoxia. Yet, the mechanisms and biological consequences of aerobic HIF1α activation by intrinsic factors, particularly in normal (primary) cells, remain elusive. Here we show that HIF1α signalling is activated in s...

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Veröffentlicht in:Nature metabolism 2024-11, Vol.6 (11), p.2138-2156
Hauptverfasser: Xiao, Wusheng, Shrimali, Nishith, Vigder, Niv, Oldham, William M., Clish, Clary B., He, Huamei, Wong, Samantha J., Wertheim, Bradley M., Arons, Elena, Haigis, Marcia C., Leopold, Jane A., Loscalzo, Joseph
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container_issue 11
container_start_page 2138
container_title Nature metabolism
container_volume 6
creator Xiao, Wusheng
Shrimali, Nishith
Vigder, Niv
Oldham, William M.
Clish, Clary B.
He, Huamei
Wong, Samantha J.
Wertheim, Bradley M.
Arons, Elena
Haigis, Marcia C.
Leopold, Jane A.
Loscalzo, Joseph
description Hypoxia-inducible factor 1α (HIF1α) is a master regulator of biological processes in hypoxia. Yet, the mechanisms and biological consequences of aerobic HIF1α activation by intrinsic factors, particularly in normal (primary) cells, remain elusive. Here we show that HIF1α signalling is activated in several human primary vascular cells in normoxia and in vascular smooth muscle cells of normal human lungs. Mechanistically, aerobic HIF1α activation is mediated by paracrine secretion of three branched-chain α-ketoacids (BCKAs), which suppress PHD2 activity via direct inhibition and via LDHA -mediated generation of L-2-hydroxyglutarate. BCKA-mediated HIF1α signalling activation stimulated glycolytic activity and governed a phenotypic switch of pulmonary artery smooth muscle cells, which correlated with BCKA metabolic dysregulation and pathophenotypic changes in pulmonary arterial hypertension patients and male rat models. We thus identify BCKAs as previously unrecognized signalling metabolites that aerobically activate HIF1α and that the BCKA–HIF1α pathway modulates vascular smooth muscle cell function, an effect that may be relevant to pulmonary vascular pathobiology. Branched-chain α-ketoacids are shown to aerobically activate HIF1α signalling, which induces a phenotypic switch in vascular smooth muscle cells that is potentially relevant in the context of pulmonary artery hypertension.
doi_str_mv 10.1038/s42255-024-01150-4
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subjects 631/443/319
631/443/592
631/443/592/75/243
631/80/86
631/80/86/2368
Amino Acids, Branched-Chain - metabolism
Animals
Biomedical and Life Sciences
Glycolysis
Humans
Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
Hypoxia-Inducible Factor-Proline Dioxygenases - metabolism
Life Sciences
Male
Muscle, Smooth, Vascular - metabolism
Myocytes, Smooth Muscle - metabolism
Pulmonary Artery - metabolism
Rats
Signal Transduction
title Branched-chain α-ketoacids aerobically activate HIF1α signalling in vascular cells
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