{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T04:11:32Z","timestamp":1790482292375,"version":"4.1.0"},"reference-count":49,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2022,8,24]],"date-time":"2022-08-24T00:00:00Z","timestamp":1661299200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deutsche Forschungsgemeinschaft","award":["GRK 2098"],"award-info":[{"award-number":["GRK 2098"]}]},{"name":"the Deutsche Herzstiftung e.V.","award":["GRK 2098"],"award-info":[{"award-number":["GRK 2098"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Altered plasma sphingosine-1-phosphate (S1P) concentrations are associated with clinical manifestations of atherosclerosis. However, whether long-term elevation of endogenous S1P is pro- or anti-atherogenic remains unclear. Here, we addressed the impact of permanently high S1P levels on atherosclerosis in cholesterol-fed apolipoprotein E-deficient (ApoE\u2212\/\u2212) mice over 12 weeks. This was achieved by pharmacological inhibition of the S1P-degrading enzyme S1P lyase with 4-deoxypyridoxine (DOP). DOP treatment dramatically accelerated atherosclerosis development, propagated predominantly unstable plaque phenotypes, and resulted in frequent plaque rupture with atherothrombosis. Macrophages from S1P lyase-inhibited or genetically deficient mice had a defect in cholesterol efflux to apolipoprotein A-I that was accompanied by profoundly downregulated cholesterol transporters ATP-binding cassette transporters ABCA1 and ABCG1. This was dependent on S1P signaling through S1PR3 and resulted in dramatically enhanced atherosclerosis in ApoE\u2212\/\u2212\/S1PR3\u2212\/\u2212 mice, where DOP treatment had no additional effect. Thus, high endogenous S1P levels promote atherosclerosis, compromise cholesterol efflux, and cause genuine plaque rupture.<\/jats:p>","DOI":"10.3390\/ijms23179606","type":"journal-article","created":{"date-parts":[[2022,8,24]],"date-time":"2022-08-24T21:03:51Z","timestamp":1661375031000},"page":"9606","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Sphingosine-1-Phosphate (S1P) Lyase Inhibition Aggravates Atherosclerosis and Induces Plaque Rupture in ApoE\u2212\/\u2212 \u00a0Mice"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6611-4121","authenticated-orcid":false,"given":"Petra","family":"Keul","sequence":"first","affiliation":[{"name":"Institute for Molecular Medicine III, University Hospital D\u00fcsseldorf, University of D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susann","family":"Peters","sequence":"additional","affiliation":[{"name":"Institute for Molecular Medicine III, University Hospital D\u00fcsseldorf, University of D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"von Wnuck Lipinski","sequence":"additional","affiliation":[{"name":"Institute for Molecular Medicine III, University Hospital D\u00fcsseldorf, University of D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7549-5325","authenticated-orcid":false,"given":"Nathalie H.","family":"Schr\u00f6der","sequence":"additional","affiliation":[{"name":"Institute for Molecular Medicine III, University Hospital D\u00fcsseldorf, University of D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6701-5539","authenticated-orcid":false,"given":"Melissa K.","family":"Nowak","sequence":"additional","affiliation":[{"name":"Institute for Molecular Medicine III, University Hospital D\u00fcsseldorf, University of D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dragos A.","family":"Duse","sequence":"additional","affiliation":[{"name":"Institute for Molecular Medicine III, University Hospital D\u00fcsseldorf, University of D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5891-9672","authenticated-orcid":false,"given":"Amin","family":"Polzin","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Pulmonology, and Vascular Medicine, Heinrich Heine University Medical Center D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Weske","sequence":"additional","affiliation":[{"name":"Institute for Molecular Medicine III, University Hospital D\u00fcsseldorf, University of D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6650-7849","authenticated-orcid":false,"given":"Markus H.","family":"Gr\u00e4ler","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine, Center for Sepsis Control and Care and Center for Molecular Biomedicine, University Hospital Jena, 07743 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bodo","family":"Levkau","sequence":"additional","affiliation":[{"name":"Institute for Molecular Medicine III, University Hospital D\u00fcsseldorf, University of D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"243","DOI":"10.3389\/fphar.2015.00243","article-title":"HDL-S1P: Cardiovascular functions, disease-associated alterations, and therapeutic applications","volume":"6","author":"Levkau","year":"2015","journal-title":"Front. 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