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| Item Type: | Article |
|---|---|
| Title: | Gut microbial metabolite imidazole propionate impairs endothelial cell function and promotes the development of atherosclerosis |
| Creators Name: | Nageswaran, V., Carreras, A., Reinshagen, L., Beck, K.R., Steinfeldt, J., Henricsson, M., Ramezani Rad, P., Peters, L., Strässler, E.T., Lim, J., Verhaar, B., Döring, Y., Weber, C., König, M., Steinhagen-Thiessen, E., Demuth, I., Kränkel, N., Leistner, D.M., Potente, M., Nieuwdorp, M., Knaus, P., Kuebler, W.M., Ferrell, M., Nemet, I., Hazen, S.L., Landmesser, U., Bäckhed, F. and Haghikia, A. |
| Abstract: | 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% CIs 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 human aortic ECs. 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 prevalent coronary artery disease. We found that ImP dose dependently impaired migratory and angiogenic properties of human ECs and promoted an increased inflammatory response. Long-term exposure to ImP compromised the repair potential of the endothelium after an arterial insult. In atheroprone Apoe(-/-) mice, ImP increased atherosclerotic lesion size. Mechanistically, ImP attenuated insulin receptor signaling by suppressing the PI3K (phosphoinositide 3-kinase)/AKT pathway leading to sustained activation of the FOXO1 (forkhead box protein O1) transcription factor. Genetic inactivation of endothelial FOXO1 signaling in ImP-treated mice enhanced the angiogenic activity and preserved the vascular repair capacity of ECs after carotid injury. CONCLUSIONS: Our findings reveal a hitherto unknown role of the microbially produced histidine-derived metabolite ImP in endothelial dysfunction and atherosclerosis, suggesting that ImP metabolism is a potential therapeutic target in atherosclerotic cardiovascular disease. |
| Keywords: | Forkhead Box Protein O1, Forkhead Transcription Factors, RNA, Small Interfering, Tamoxifen, Vascular System Injuries, Animals, Mice |
| Source: | Arteriosclerosis Thrombosis and Vascular Biology |
| ISSN: | 1079-5642 |
| Publisher: | American Heart Association |
| Date: | 27 March 2025 |
| Official Publication: | https://doi.org/10.1161/atvbaha.124.322346 |
| PubMed: | View item in PubMed |
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