Endothelial monocarboxylate transporter 1 drives atherosclerosis via a lactate/NADH/CtBP‐mediated transrepression pathway

The accumulation of lactate in tissue microenvironments is associated with atherosclerosis, but its precise role in atherogenesis remains largely unknown. This study demonstrated that lactate accumulation in aortic tissues and blood is correlated with increased monocarboxylate transporter 1 (Mct1) expression in endothelial cells (ECs) within atherosclerotic plaques. Lactate uptake via Mct1 triggers an inflammatory response in ECs. The administration of endothelial-targeting nanoparticles containing siRNA against <i>Mct1</i> reduces endothelial inflammation and atherogenesis in <i>Apoe^-/-</i> mice. Mechanistic studies revealed that the conversion of lactate to pyruvate, along with NADH production and oligomerization of the NADH-sensitive transcriptional corepressor C-terminal binding protein 1 (CtBP1), is necessary for the proinflammatory effects of lactate. Monomeric CtBP1 interacts with the transcriptional repressor forkhead box P1 (FOXP1) to suppress endothelial adhesion molecule expression. However, NADH-induced oligomerization of CtBP1 prevents its binding to FOXP1, significantly reducing FOXP1-mediated transrepression of endothelial adhesion molecules. Moreover, silencing <i>Foxp1</i> in ECs negates the atheroprotective effect of endothelial <i>Mct1</i> knockdown in <i>Apoe^-/-</i> mice. These findings suggest that lactate/MCT1-induced epigenetic reprogramming represents a potential therapeutic target in atherosclerosis.