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

Autor: Xiao W; Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.; Department of Toxicology, School of Public Health, Peking University, Beijing, China.; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, School of Public Health, Peking University, Beijing, China.; Key Laboratory of State Administration of Traditional Chinese Medicine for Compatibility Toxicology, School of Public Health, Peking University, Beijing, China., Shrimali N; Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Vigder N; Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.; School of Life and Environmental Sciences, Faculty of Science, The University of Sydney, Sydney, NSW, Australia., Oldham WM; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Clish CB; Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA., He H; Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Wong SJ; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA., Wertheim BM; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Arons E; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Haigis MC; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA., Leopold JA; Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Loscalzo J; Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. jloscalzo@rics.bwh.harvard.edu.
Jazyk: angličtina
Zdroj: Nature metabolism [Nat Metab] 2024 Oct 29. Date of Electronic Publication: 2024 Oct 29.
DOI: 10.1038/s42255-024-01150-4
Abstrakt: 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.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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