Gut microbial metabolite imidazole propionate impairs endothelial cell function and promotes the development of atherosclerosis

Nageswaran, V.; Carreras, A.; Reinshagen, L.; Beck, K. R.; Steinfeldt, J.; Stahlman, M.; Ramezani Rad, P.; Lim, J.; Strässler, E. T.; Verhaar, B. J. H.; Döring, Y.; Weber, C.; König, M.; Steinhagen-thiessen, E.; Demuth, I.; Kränkel, N.; Leistner, D. M.; Nieuwdorp, M.; Knaus, P.; Ferrell, M.; Potente, M.; Hazen, S. L.; Landmesser, U.; Bäckhed, F.; Haghikia, A.

doi:10.1101/2024.06.05.597678

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bioRxiv · 10.1101/2024.06.05.597678

Gut microbial metabolite imidazole propionate impairs endothelial cell function and promotes the development of atherosclerosis

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Abstract

BackgroundThe 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. Using both human and animal model studies, we investigated the potential contributory role of ImP in the development of atherosclerosis. MethodsPlasma levels of ImP were measured in patients undergoing elective cardiac angiography (n = 831) by means of ultra high-performance liquid chromatography coupled to tandem mass spectrometry. Odds ratios (ORs) and corresponding 95% confidence intervals for CAD were calculated based on the ImP quartiles using both univariable and multivariable logistic regression models. Atheroprone apolipoprotein E-/- (Apoe-/-) mice fed a high-fat diet were additionally treated with ImP (800 {micro}g) or vehicle and aortic atherosclerotic lesion area was evaluated after 12 weeks. In a mouse model of carotid artery injury, the effect of ImP on vascular regeneration was examined. Using human aortic endothelial cells (HAECs) the effect of ImP on functional properties of endothelial cells were assessed. Next-generation sequencing, western blot analysis, siRNA-based gene knockdown and tamoxifen-inducible Cre-loxP experiments were performed to investigate ImP-mediated molecular mechanisms. ResultsPlasma ImP levels in subjects undergoing cardiac evaluation were associated with increased risk for prevalent CAD. In atheroprone Apoe-/- mice ImP increased atherosclerotic lesion size. We found that ImP dose-dependently impaired migratory and angiogenic properties of human endothelial cells, and promoted an increased inflammatory response. Long-term exposure to ImP impaired the repair potential of the endothelium after an arterial insult. Mechanistically, ImP attenuated insulin receptor signaling by suppressing PI3K/AKT pathway leading to the sustained activation of the forkhead box protein O1 (FOXO1) transcription factor. Genetic inactivation of endothelial FOXO1 signaling in ImP-treated mice enhanced the angiogenic activity and preserved the vascular repair capacity of endothelial cells after carotid injury. ConclusionsOur 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.

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Nageswaran, V., Carreras, A., Reinshagen, L., Beck, K. R., Steinfeldt, J., Stahlman, M., Ramezani Rad, P., Lim, J., Strässler, E. T., Verhaar, B. J. H., Döring, Y., Weber, C., König, M., Steinhagen-thiessen, E., Demuth, I., Kränkel, N., Leistner, D. M., Nieuwdorp, M., Knaus, P., Ferrell, M., Potente, M., Hazen, S. L., Landmesser, U., Bäckhed, F., Haghikia, A.. 2024-06-10. Gut microbial metabolite imidazole propionate impairs endothelial cell function and promotes the development of atherosclerosis. https://doi.org/10.1101/2024.06.05.597678

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