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

Abstract

Abstract Increased mitochondrial reactive oxygen species (mROS) and glycolysis have been established in pulmonary hypertension (PH). However, the effect of elevated mROS on glycolytic shift along with how increased glycolysis promotes hypoxic pulmonary artery smooth muscle cells (PASMCs) proliferation and vascular remodeling remain elusive. Here, we reported that hypoxia-induced mROS inhibit HIF-1α hydroxylation and further trigger PASMCs glycolytic switch through the upregulated HIF-1α/PDK1&2/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 PASMCs proliferation. Knockdown of Pdk1&2 blunts lactate production, histone lactylation marks, and PASMCs proliferation. Moreover, pharmacological intervention with lactate dehydrogenase inhibitor diminishes histone lactylation and ameliorates PASMCs proliferation and vascular remodeling in hypoxic PH rats. Taken together, this study provides proof of concept for anti-remodeling therapy through lactate manipulation.