IDH2-K272 lactylation ameliorates diabetic atherosclerosis by stabilizing endothelial function via α-ketoglutarate

Absrtact Atherosclerosis (AS) constitutes the primary underlying etiology of cardiovascular diseases (CVDs), and diabetes mellitus exacerbates the risk of mortality and disability in patients with AS-related CVDs. Given the pivotal role of endothelial cell dysfunction in the progression of diabetic AS plaques, our series of studies has identified that endothelial IDH2 lactylation exerts a cardiovascular protective effect. Lysine residue 272 serves as the specific lactylation site, and the level of this modification is significantly elevated in diabetic plaques. Furthermore, adenovirus was used to infect mouse aortic endothelial cells (MAECs) to abrogate the lactylation activity at the K272 site of IDH2. Experimental results demonstrated that IDH2-K272 lactylation contributes to the maintenance of IDH2 enzymatic activity, thereby ensuring sufficient biosynthesis of α-ketoglutarate (α-KG) and attenuating mitochondrial damage and endothelial dysfunction under hyperglycemic and hyperlipidemic conditions. Additionally, utilizing adeno-associated viruses encoding the K272 site (AAV ENT -IDH2-K272R) to abrogate endothelial IDH2 lactylation activity of ApoE –/– male mice, we induced diabetic plaques with streptozotocin (STZ). Concurrently, in endothelial cell-specific IDH2-K272R knock-in (IDH2 EC-K272R ) male mice, plaques were induced using AAV-PCSK9 and STZ. Both animal models consistently demonstrated that loss of K272 lactylation exacerbates mitochondrial dysfunction and endothelial injury, thereby promoting plaque formation and instability. Furthermore, we validated that exogenous supplementation of α-KG effectively mitigates the progression of diabetic plaques. In summary, our study is the first to reveal that endothelial IDH2-K272 lactylation counteracts diabetic atherosclerosis via α-KG, thereby offering a valuable therapeutic strategy.