Chen Ai, Chen Zhihai, Huang Bangbang, Lian Guili, Luo Li, Xie Liangdi
Department of Geriatrics, The First Affiliated Hospital of Fujian Medical University, 20 Chazhong Road, Fuzhou, 350005, China.
Fujian Hypertension Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China.
Mol Cell Biochem. 2025 Jun 30. doi: 10.1007/s11010-025-05342-8.
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.
肺动脉高压（PH）的特征是肺血管重塑和肺动脉平滑肌细胞（PASMCs）过度增殖。糖酵解在PH发病机制中起关键作用，但将糖酵解与PASMCs增殖联系起来的表观遗传机制仍不清楚。组蛋白乳酸化是一种源自糖酵解乳酸的新型翻译后修饰，可能调节PASMCs增殖。将原代大鼠PASMCs在缺氧条件下培养并用L-乳酸钠（NaLa）处理，以评估糖酵解活性和组蛋白乳酸化。RNA测序、RT-qPCR和蛋白质免疫印迹法鉴定差异表达基因（DEGs），而染色质免疫沉淀-定量PCR（ChIP-qPCR）评估基因启动子处的组蛋白乳酸化富集情况。在体内，使用缺氧诱导的PH大鼠模型来研究用草氨酸抑制糖酵解的效果。孟德尔随机化（MR）分析评估胎盘生长因子（PGF）与PH之间的因果关系。缺氧和NaLa处理显著增加了糖酵解活性、乳酸生成和组蛋白乳酸化，促进了PASMCs增殖。转录组分析鉴定出157个DEGs，其中五个关键基因（Gbe1、Pgf、Mt2A、Ythdf2和Gys1）在组蛋白乳酸化反应中上调。ChIP-qPCR证实其启动子处有H3K18la富集。用草氨酸抑制糖酵解可有效降低缺氧PH大鼠的组蛋白乳酸化、PASMCs增殖和血管重塑。MR分析确定PGF是导致PH风险的一个因果因素，提示了一个潜在的治疗靶点。这项研究表明，糖酵解诱导的组蛋白乳酸化驱动了PH中PASMCs的增殖和血管重塑。针对乳酸代谢和组蛋白乳酸化可能提供一种新的治疗方法。
