Hypoxia-induced histone lactylation promotes pulmonary arterial smooth muscle cells proliferation in pulmonary hypertension

Pulmonary hypertension (PH) is characterized by pulmonary vascular remodeling and excessive proliferation of pulmonary artery smooth muscle cells (PASMCs). Glycolysis plays a crucial role in PH pathogenesis, but the epigenetic mechanisms linking glycolysis to PASMCs proliferation remain unclear. Histone lactylation, a novel post-translational modification derived from glycolytic lactate, may regulate PASMCs proliferation. Primary rat PASMCs were cultured under hypoxia and treated with sodium L-lactate (NaLa) to assess glycolytic activity and histone lactylation. RNA sequencing, RT-qPCR, and Western blotting identified differentially expressed genes (DEGs), while ChIP-qPCR evaluated histone lactylation enrichment at gene promoters. In vivo, a hypoxia-induced PH rat model was used to examine the effect of glycolysis inhibition using oxamate. Mendelian randomization (MR) analysis assessed the causal relationship between placental growth factor (PGF) and PH. Hypoxia and NaLa treatment significantly increased glycolytic activity, lactate production, and histone lactylation, promoting PASMCs proliferation. Transcriptomic analysis identified 157 DEGs, with five key genes (Gbe1, Pgf, Mt2A, Ythdf2 and Gys1) upregulated in response to histone lactylation. ChIP-qPCR confirmed H3K18la enrichment at their promoters. Glycolysis inhibition with oxamate effectively reduced histone lactylation, PASMCs proliferation, and vascular remodeling in hypoxic PH rats. MR analysis identified PGF as a causal factor contributing to PH risk, suggesting a potential therapeutic target. This study reveals that glycolysis-induced histone lactylation drives PASMCs proliferation and vascular remodeling in PH. Targeting lactate metabolism and histone lactylation may provide a novel therapeutic approach.