Histone lactylation driven by mROS-mediated glycolytic shift promotes hypoxic pulmonary hypertension

作者：Jian Chen, Meiling Zhang, Yanjie Liu, Shihong Zhao, Yanxia Wang, Meng Wang, Wen Niu, Faguang Jin, Zhichao Li · 发表于：Journal of Molecular Cell Biology · 年份：2022 · DOI：10.1093/jmcb/mjac073 · 被引用次数：127 · 研究领域：Cancer, Hypoxia, and Metabolism、RNA modifications and cancer、Mitochondrial Function and Pathology

Increased mitochondrial reactive oxygen species (mROS) and glycolysis have been established in pulmonary hypertension (PH). However, the effect of elevated mROS on glycolytic shift and how increased glycolysis promotes hypoxic pulmonary artery smooth muscle cell (PASMC) proliferation and vascular remodeling remain elusive. Here, we reported that hypoxia-induced mROS inhibit HIF-1α hydroxylation and further trigger PASMC glycolytic switch through the upregulated HIF-1α/PDK1&PDK2/p-PDH-E1α axis, which facilitates lactate accumulation and histone lactylation. Through H3K18la and HIF-1α ChIP-seq analysis, we found that the enhanced histone lactylation of HIF-1α targets, such as Bmp5, Trpc5, and Kit, promotes PASMC proliferation. Knockdown of Pdk1&2 blunts lactate production, histone lactylation marks, and PASMC proliferation. Moreover, pharmacological intervention with lactate dehydrogenase inhibitor diminishes histone lactylation and ameliorates PASMC proliferation and vascular remodeling in hypoxic PH rats. Taken together, this study provides proof of concept for anti-remodeling therapy through lactate manipulation.