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 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.
Competing Interests: Competing interests: J.L. discloses scientific board/board relationships with Ionis (outside the scope of the current topic), Leap Therapeutics (outside the scope of the current topic) and Scipher Medicine (outside the scope of the current topic). B.M.W. discloses a consulting relationship with Change Healthcare (outside the scope of the current topic), an expert witness relationship with United Therapeutics Corporation (outside the scope of the current topic) and co-inventorship on US patent 63/541,939 (outside the scope of the current topic). All other authors declare no competing interests.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)