糖酵解
组蛋白
厌氧糖酵解
缺氧(环境)
乳酸脱氢酶A
细胞生物学
乳酸脱氢酶
化学
下调和上调
癌症研究
生物化学
生物
新陈代谢
氧气
酶
基因
有机化学
作者
Jian Chen,Meiling Zhang,Yanjie Liu,S H Zhao,Yanxia Wang,Meng Wang,Wen Niu,Fengliang Jin,Zhichao Li
摘要
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 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.
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