TMAO induces pyroptosis of vascular endothelial cells and atherosclerosis in ApoE−/− mice via MBOAT2-mediated endoplasmic reticulum stress

Trimethylamine N-oxide (TMAO), a metabolite produced by intestinal flora, is recognized as an independent risk factor for atherosclerosis and atherosclerotic cardiovascular diseases. However, the underlying mechanism remains poorly understood. Here, we showed that dietary TMAO supplementation accelerates atherosclerosis in ApoE −/− mice. Pyroptosis and the expression of phospholipid-modifying enzyme MBOAT2 were increased in endothelial cells within atherosclerotic lesions. Genetic upregulation of MBOAT2 via adeno-associated virus with endothelium-specific promoter results in increased atherosclerotic lesions in ApoE −/− mice. Mechanistically, the overexpression of MBOAT2 disrupted glycerophospholipid metabolism and induced endothelial cell pyroptosis in an Endoplasmic reticulum stress-dependent manner. These data reveal that TMAO promotes endothelial cell pyroptosis and the progression of atherosclerotic lesions through the upregulation of MBOAT2, indicating that MBOAT2 is a promising therapeutic target for atherosclerosis. • TMAO promotes vascular endothelial cell pyroptosis and the progression of atherosclerosis. • The overexpression of phospholipid-modifying enzyme MBOAT2 promotes to endothelial cell ER stress and pyroptosis and AS. • The TMAO-induced endothelial cells pyroptosis is mediated by ER stress.