Gut Microbial Metabolite Imidazole Propionate Impairs Endothelial Cell Function and Promotes the Development of Atherosclerosis

作者：Vanasa Nageswaran, Alba Carreras, Leander Reinshagen, Katharina R. Beck, Jakob Steinfeldt, Marcus Henricsson, Pegah Ramezani Rad, Lisa Peters, Elisabeth Strässler, J.J. Lim, Barbara J. H. Verhaar, Yvonne Döring, C. Weber, Maximilian König, Elisabeth Steinhagen–Thiessen, Ilja Demuth, N Kraenkel, David M. Leistner, Michael Potente, Max Nieuwdorp, Petra Knaus, Wolfgang M. Kuebler, Marc Ferrell, Ina Nemet, Stanley L. Hazen, Ulf Landmesser, Fredrik Bäckhed, Arash Haghikia · 发表于：Arteriosclerosis Thrombosis and Vascular Biology · 年份：2025 · DOI：10.1161/atvbaha.124.322346 · 被引用次数：37 · 研究领域：FOXO transcription factor regulation、Microbial Metabolism and Applications、Adipokines, Inflammation, and Metabolic Diseases

BACKGROUND: The microbially produced amino acid–derived metabolite imidazole propionate (ImP) contributes to the pathogenesis of type 2 diabetes. However, the effects of ImP on endothelial cell (EC) physiology and its role in atherosclerotic coronary artery disease are unknown. Using both human and animal model studies, we investigated the potential contributory role of ImP in the development of atherosclerosis. METHODS: Plasma levels of ImP were measured in patients undergoing elective cardiac angiography (n=831) by ultra-high performance liquid chromatography coupled to tandem mass spectrometry. Odds ratios and corresponding 95% confidence intervals for coronary artery disease were calculated based on the ImP quartiles using both univariable and multivariable logistic regression models. The effects of ImP on functional properties of ECs were assessed using HAECs (human aortic endothelial cells). In a mouse model of carotid artery injury, the impact of ImP on vascular regeneration was examined. Additionally, atheroprone Apoe −/− mice fed a high-fat diet were treated with and without ImP (800 µg), and aortic atherosclerotic lesion area was evaluated after 12 weeks. Next-generation sequencing, Western blot analysis, small interfering RNA–based gene knockdown, and tamoxifen-inducible Cre-loxP experiments were performed to investigate ImP-mediated molecular mechanisms. RESULTS: Plasma ImP levels in subjects undergoing cardiac evaluation were associated with increased risk of pre...