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.
Nat Metab. 2024 Nov;6(11):2138-2156. doi: 10.1038/s42255-024-01150-4. Epub 2024 Oct 29.
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.
缺氧诱导因子 1α（HIF1α）是缺氧条件下生物过程的主要调节因子。然而，内在因素（尤其是在正常（原代）细胞中）有氧激活 HIF1α的机制和生物学后果仍不清楚。在这里，我们发现在常氧条件下，几种人原代血管细胞和正常人肺部的血管平滑肌细胞中激活了 HIF1α信号通路。从机制上讲，有氧 HIF1α的激活是通过旁分泌三种支链α-酮酸（BCKA）来介导的，通过直接抑制和通过 LDHA 介导的 L-2-羟基戊二酸的生成来抑制 PHD2 的活性。BCKA 介导的 HIF1α信号通路的激活刺激了糖酵解活性，并调控了肺动脉平滑肌细胞的表型转换，这与 BCKA 代谢失调以及肺动脉高压患者和雄性大鼠模型的病理表型变化相关。因此，我们将 BCKA 鉴定为先前未被识别的信号代谢物，其可在有氧条件下激活 HIF1α，而 BCKA-HIF1α 通路调节血管平滑肌细胞功能，这种作用可能与肺血管病理生理学相关。
