IDH2 lactylation promotes angiogenesis in murine diabetic myocardial infarction via blocking Cav1-eNOS interaction.

Compensatory angiogenesis is critical for preserving left ventricular function after myocardial infarction; however, this process is severely impaired in diabetes, exacerbating adverse outcomes in diabetic myocardial infarction (DMI). This study employed liquid chromatography-tandem mass spectrometry to identify lactylated proteins in the infarct border zone of DMI male mouse hearts. Our findings revealed that IDH2 is lactylated at lysine 272, enhancing its binding to Cav1 while inhibiting the Cav1-eNOS interaction. This modification promotes eNOS activity and facilitates the proliferation, migration, and angiogenesis of cardiac microvascular endothelial cells under high glucose and hypoxic conditions. In endothelial cell-specific IDH2-K272R knock-in male mice, the loss of K272 lactylation impairs cardiac function and exacerbates pathological remodeling due to disrupted angiogenesis. Additionally, ACAT1 and HDAC1 act as lactyltransferase and delactylase, respectively, utilizing intracellular lactate transported via MCT1 as a substrate for IDH2 lactylation. Furthermore, pharmacologic enhancement of IDH2 lactylation, as demonstrated by empagliflozin mitigating post-DMI injury, supports its potential as a therapeutic target for DMI.