Imidazole propionate (ImP): effect on human aortic endothelial cells

The microbially generated amino acid-derived metabolite imidazole propionate (ImP) contributes to the pathogenesis of type 2 diabetes. However, the effect of ImP on endothelial cell physiology and its role in atherosclerotic coronary artery disease (CAD) is unknown. Here we demonstrate for the first time that plasma ImP levels in subjects undergoing cardiac evaluation (n = 833) predict increased risks for prevalent CAD. In atheroprone apolipoprotein E-/- (Apoe-/-) mice ImP increased atherosclerotic lesion size. We found that ImP dose-dependently impaired migratory and angiogenic properties of human endothelial cells (EC) with increased inflammatory response. In a mouse model of carotid injury, chronic exposure of ImP impaired repair potential of the endothelium after injury. Mechanistically, ImP attenuated insulin receptor signaling by suppressing PI3K/AKT pathway with subsequent disinhibition of forkhead box protein O1 (FOXO1) transcription factor. Our findings reveal a novel mechanism that associates the microbially produced histidine-derived metabolite ImP to dysfunctional endothelium and increased atherosclerosis, suggesting to target ImP production as a potential strategy to prevent atherosclerotic cardiovascular disease.