{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T05:25:43Z","timestamp":1793510743651,"version":"4.5.0"},"reference-count":52,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2025,5,1]],"date-time":"2025-05-01T00:00:00Z","timestamp":1746057600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>The microbially produced amino acid\u2013derived 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>Apoe<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      mice fed a high-fat diet were treated with and without ImP (800 \u00b5g), and aortic atherosclerotic lesion area was evaluated after 12 weeks. Next-generation sequencing, Western blot analysis, small interfering RNA\u2013based gene knockdown, and tamoxifen-inducible Cre-loxP experiments were performed to investigate ImP-mediated molecular mechanisms.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>Apoe<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      (apolipoprotein E\n                      <jats:sup>\n                        <jats:italic>\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      ) 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/atvbaha.124.322346","type":"journal-article","created":{"date-parts":[[2025,3,27]],"date-time":"2025-03-27T05:03:36Z","timestamp":1743051816000},"page":"823-839","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":50,"title":["Gut Microbial Metabolite Imidazole Propionate Impairs Endothelial Cell Function and Promotes the Development of Atherosclerosis"],"prefix":"10.1161","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4738-2558","authenticated-orcid":true,"given":"Vanasa","family":"Nageswaran","sequence":"first","affiliation":[{"name":"Department of Cardiology, Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charit\u00e9, Campus Benjamin Franklin, Berlin, Germany (V.N., L.R., J.S., P.R.R., E.T.S., N.K., U.L., A.H.)."},{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Germany (V.N., L.R., P.R.R., L.P., E.T.S., N.K., M.P., W.M.K., U.L., A.H.)."},{"name":"Friede Springe-Cardiovascular Prevention Center at Charit\u00e9, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Germany (V.N., J.S., E.S.-T., N.K., U.L., A.H.)."},{"name":"Institute of Chemistry and Biochemistry, Freie Universit\u00e4t Berlin, Germany (V.N., P.K.)."},{"name":"University Hospital St. Josef-Hospital Bochum, Cardiology and Rhythmology, Ruhr University Bochum, Germany (V.N., L.R., A.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8787-8833","authenticated-orcid":true,"given":"Alba","family":"Carreras","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Sahlgrenska University Hospital, University of Gothenburg, Sweden (A.C., K.R.B., M.H., F.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9137-5667","authenticated-orcid":true,"given":"Leander","family":"Reinshagen","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charit\u00e9, Campus Benjamin Franklin, Berlin, Germany (V.N., L.R., J.S., P.R.R., E.T.S., N.K., U.L., A.H.)."},{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Germany (V.N., L.R., P.R.R., L.P., E.T.S., N.K., M.P., W.M.K., U.L., A.H.)."},{"name":"University Hospital St. Josef-Hospital Bochum, Cardiology and Rhythmology, Ruhr University Bochum, Germany (V.N., L.R., A.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9818-1265","authenticated-orcid":true,"given":"Katharina R.","family":"Beck","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Sahlgrenska University Hospital, University of Gothenburg, Sweden (A.C., K.R.B., M.H., F.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1387-2054","authenticated-orcid":true,"given":"Jakob","family":"Steinfeldt","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charit\u00e9, Campus Benjamin Franklin, Berlin, Germany (V.N., L.R., J.S., P.R.R., E.T.S., N.K., U.L., A.H.)."},{"name":"Friede Springe-Cardiovascular Prevention Center at Charit\u00e9, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Germany (V.N., J.S., E.S.-T., N.K., U.L., A.H.)."},{"name":"Berlin Institute of Health at Charit\u00e9-Universit\u00e4tsmedizin Berlin, Germany (J.S., U.L., A.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4202-0339","authenticated-orcid":true,"given":"Marcus","family":"Henricsson","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Sahlgrenska University Hospital, University of Gothenburg, Sweden (A.C., K.R.B., M.H., F.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6697-9149","authenticated-orcid":true,"given":"Pegah","family":"Ramezani Rad","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charit\u00e9, Campus Benjamin Franklin, Berlin, Germany (V.N., L.R., J.S., P.R.R., E.T.S., N.K., U.L., A.H.)."},{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Germany (V.N., L.R., P.R.R., L.P., E.T.S., N.K., M.P., W.M.K., U.L., A.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3157-6590","authenticated-orcid":true,"given":"Lisa","family":"Peters","sequence":"additional","affiliation":[{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Germany (V.N., L.R., P.R.R., L.P., E.T.S., N.K., M.P., W.M.K., U.L., A.H.)."},{"name":"Institute of Physiology, Charit\u00e9-Universit\u00e4tsmedizin Berlin, corporate member of the Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, Germany (L.P., W.M.K.)."},{"name":"Institute of Biology, Freie Universit\u00e4t Berlin, Germany (L.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5286-9686","authenticated-orcid":true,"given":"Elisabeth T.","family":"Str\u00e4ssler","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charit\u00e9, Campus Benjamin Franklin, Berlin, Germany (V.N., L.R., J.S., P.R.R., E.T.S., N.K., U.L., A.H.)."},{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Germany (V.N., L.R., P.R.R., L.P., E.T.S., N.K., M.P., W.M.K., U.L., A.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1740-8710","authenticated-orcid":true,"given":"Joseph","family":"Lim","sequence":"additional","affiliation":[{"name":"Angiogenesis and Metabolism Laboratory, Berlin Institute of Health at Charit\u00e9-Universit\u00e4tsmedizin Berlin, Germany (J.L., M.P.)."},{"name":"Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (J.L., M.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7941-6110","authenticated-orcid":true,"given":"Barbara J.H.","family":"Verhaar","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine-Geriatrics, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center (UMC), the Netherlands (B.J.H.V., M.N.)."},{"name":"Department of Vascular Medicine, Amsterdam UMC, the Netherlands (B.J.H.V., M.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9307-3396","authenticated-orcid":true,"given":"Yvonne","family":"D\u00f6ring","sequence":"additional","affiliation":[{"name":"Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilian University of Munich, Germany (Y.D., C.W.)."},{"name":"Division of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of Bern, Switzerland (Y.D.)"},{"name":"Department for BioMedical Research (DBMR), University of Bern, Switzerland (Y.D.)."},{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Munich, Germany (Y.D., C.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7676-1223","authenticated-orcid":true,"given":"Christian","family":"Weber","sequence":"additional","affiliation":[{"name":"Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilian University of Munich, Germany (Y.D., C.W.)."},{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Munich, Germany (Y.D., C.W.)."},{"name":"Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, the Netherlands (C.W.)."},{"name":"Munich Cluster for Systems Neurology, Germany (C.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4873-5519","authenticated-orcid":true,"given":"Maximilian","family":"K\u00f6nig","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine D\u2013Geriatrics, University Medicine Greifswald, Germany (M.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3056-3317","authenticated-orcid":true,"given":"Elisabeth","family":"Steinhagen-Thiessen","sequence":"additional","affiliation":[{"name":"Friede Springe-Cardiovascular Prevention Center at Charit\u00e9, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Germany (V.N., J.S., E.S.-T., N.K., U.L., A.H.)."},{"name":"Department of Endocrinology and Metabolic Diseases (including Division of Lipid Metabolism), Charit\u00e9-Universit\u00e4tsmedizin Berlin, corporate member of the Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, Germany (E.S.-T., I.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4340-2523","authenticated-orcid":true,"given":"Ilja","family":"Demuth","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolic Diseases (including Division of Lipid Metabolism), Charit\u00e9-Universit\u00e4tsmedizin Berlin, corporate member of the Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, Germany (E.S.-T., I.D.)."},{"name":"Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Berlin Institute of Health Center for Regenerative Therapies, Germany (I.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9363-1770","authenticated-orcid":true,"given":"Nicolle","family":"Kr\u00e4nkel","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charit\u00e9, Campus Benjamin Franklin, Berlin, Germany (V.N., L.R., J.S., P.R.R., E.T.S., N.K., U.L., A.H.)."},{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Germany (V.N., L.R., P.R.R., L.P., E.T.S., N.K., M.P., W.M.K., U.L., A.H.)."},{"name":"Friede Springe-Cardiovascular Prevention Center at Charit\u00e9, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Germany (V.N., J.S., E.S.-T., N.K., U.L., A.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4351-420X","authenticated-orcid":true,"given":"David M.","family":"Leistner","sequence":"additional","affiliation":[{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Frankfurt Rhine-Main, Germany (D.M.L.)."},{"name":"Department of Medicine, Cardiology and Angiology, Goethe University Hospital, Frankfurt, Germany (D.M.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Potente","sequence":"additional","affiliation":[{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Germany (V.N., L.R., P.R.R., L.P., E.T.S., N.K., M.P., W.M.K., U.L., A.H.)."},{"name":"Angiogenesis and Metabolism Laboratory, Berlin Institute of Health at Charit\u00e9-Universit\u00e4tsmedizin Berlin, Germany (J.L., M.P.)."},{"name":"Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (J.L., M.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max","family":"Nieuwdorp","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine-Geriatrics, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center (UMC), the Netherlands (B.J.H.V., M.N.)."},{"name":"Department of Vascular Medicine, Amsterdam UMC, the Netherlands (B.J.H.V., M.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2492-1667","authenticated-orcid":true,"given":"Petra","family":"Knaus","sequence":"additional","affiliation":[{"name":"Institute of Chemistry and Biochemistry, Freie Universit\u00e4t Berlin, Germany (V.N., P.K.)."},{"name":"Berlin-Brandenburg School for Regenerative Therapies, Germany (P.K.)."},{"name":"International Max-Planck Research School for Biology and Computation, Berlin, Germany (P.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4100-2961","authenticated-orcid":true,"given":"Wolfgang M.","family":"Kuebler","sequence":"additional","affiliation":[{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Germany (V.N., L.R., P.R.R., L.P., E.T.S., N.K., M.P., W.M.K., U.L., A.H.)."},{"name":"Institute of Physiology, Charit\u00e9-Universit\u00e4tsmedizin Berlin, corporate member of the Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, Germany (L.P., W.M.K.)."},{"name":"German Center for Lung Research (DZL), Berlin, Germany (W.M.K.)."},{"name":"Keenan Research Centre for Biomedical Science at St. Michael\u2019s, Toronto, Canada (W.M.K.)."},{"name":"Departments of Surgery and Physiology, University of Toronto, Canada (W.M.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2460-5659","authenticated-orcid":true,"given":"Marc","family":"Ferrell","sequence":"additional","affiliation":[{"name":"Departments of Cardiovascular and Metabolic Sciences, and Cardiovascular Medicine, Cleveland Clinic, OH (M.F., I.N., S.L.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0657-7121","authenticated-orcid":true,"given":"Ina","family":"Nemet","sequence":"additional","affiliation":[{"name":"Departments of Cardiovascular and Metabolic Sciences, and Cardiovascular Medicine, Cleveland Clinic, OH (M.F., I.N., S.L.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7124-6639","authenticated-orcid":true,"given":"Stanley L.","family":"Hazen","sequence":"additional","affiliation":[{"name":"Departments of Cardiovascular and Metabolic Sciences, and Cardiovascular Medicine, Cleveland Clinic, OH (M.F., I.N., S.L.H.)."},{"name":"Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University School of Medicine, OH (S.L.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0214-3203","authenticated-orcid":true,"given":"Ulf","family":"Landmesser","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charit\u00e9, Campus Benjamin Franklin, Berlin, Germany (V.N., L.R., J.S., P.R.R., E.T.S., N.K., U.L., A.H.)."},{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Germany (V.N., L.R., P.R.R., L.P., E.T.S., N.K., M.P., W.M.K., U.L., A.H.)."},{"name":"Friede Springe-Cardiovascular Prevention Center at 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