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

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-1αhydroxylation and further trigger PASMC glycolytic switch through the upregulated HIF-1α/PDK1&PDK2/p-PDH-E1αaxis,which facilitates lactate accumulation and histone lactylation.Through H3K18la and HIF-1αChIP–seq analysis,we found that the enhanced histone lactylation of HIF-1αtargets,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.

ASF1A-dependent P300-mediated histone H3 lysine 18 lactylation promotes atherosclerosis by regulating EndMT

Endothelial-to-mesenchymal transition(EndMT)is a key driver of atherosclerosis.Aerobic glycolysis is increased in the endothelium of atheroprone areas,accompanied by elevated lactate levels.Histone lactylation,mediated by lactate,can regulate gene expression and participate in disease regulation.However,whether histone lactylation is involved in atherosclerosis remains unknown.Here,we report that lipid peroxidation could lead to EndMT-induced atherosclerosis by increasing lactatedependent histone H3 lysine 18 lactylation(H3K18la)in vitro and in vivo,as well as in atherosclerotic patients’arteries.Mechanistically,the histone chaperone ASF1A was first identified as a cofactor of P300,which precisely regulated the enrichment of H3K18la at the promoter of SNAI1,thereby activating SNAI1 transcription and promoting EndMT.We found that deletion of ASF1A inhibited EndMT and improved endothelial dysfunction.Functional analysis based on Apoe^(KO)Asf1a^(ECKO) mice in the atherosclerosis model confirmed the involvement of H3K18la in atherosclerosis and found that endotheliumspecific ASF1A deficiency inhibited EndMT and alleviated atherosclerosis development.Inhibition of glycolysis by pharmacologic inhibition and advanced PROTAC attenuated H3K18la,SNAI1 transcription,and EndMT-induced atherosclerosis.This study illustrates precise crosstalk between metabolism and epigenetics via H3K18la by the P300/ASF1A molecular complex during EndMT-induced atherogenesis,which provides emerging therapies for atherosclerosis.