{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T17:33:40Z","timestamp":1792604020658,"version":"4.5.0"},"reference-count":68,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2025,1,28]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Aortic valve disease (AVD) is associated with high mortality and morbidity. To date, there is no pharmacological therapy available to prevent AVD progression. Because valve calcification is the hallmark of AVD and S1P (sphingosine-1-phosphate) plays an important role in osteogenic signaling, we examined the role of S1P signaling in aortic stenosis disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>AVD progression and its consequences for cardiac function were examined in a murine wire injury\u2013induced AVD model with and without pharmacological and genetic modulation of S1P production, degradation, and receptor signaling. S1P was measured by liquid chromatography-mass spectrometry. Calcification of human valvular interstitial cells and their response to biomechanical stress were analyzed in the context of S1P signaling. Human explanted aortic valves from patients undergoing aortic valve replacement and cardiovascular magnetic resonance imaging were analyzed for S1P by liquid chromatography-mass spectrometry.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>Raising S1P concentrations in mice with injury-induced AVD by pharmacological inhibition of its sole degrading enzyme S1P lyase vastly enhanced AVD progression and impaired cardiac function resembling human disease. In contrast, low S1P levels caused by SphK1 (sphingosine kinase 1) deficiency potently attenuated AVD progression. We found S1P\/S1PR2 (S1P receptor 2) signaling to be responsible for the adverse S1P effect because S1PR2-deficient mice were protected against AVD progression and its deterioration by high S1P. It is important to note that pharmacological S1PR2 inhibition administered after wire injury successfully prevented AVD development. Mechanistically, biomechanical stretch stimulated S1P production by SphK1 in human valvular interstitial cells as measured by C17-S1P generation, whereas S1P\/S1PR2 signaling induced their osteoblastic differentiation and calcification through osteogenic RUNX2\/OPG signaling and the GSK3\u03b2-Wnt-\u03b2-catenin pathway. In patients with AVD, stenotic valves exposed to high wall shear stress had higher S1P content and increased SphK1 expression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Increased systemic or local S1P levels lead to increased valvular calcification. S1PR2 antagonists and SphK1 inhibitors may offer feasible pharmacological approaches to human AVD in prophylactic, disease-modifying or relapse-preventing manners.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.123.067270","type":"journal-article","created":{"date-parts":[[2024,10,21]],"date-time":"2024-10-21T05:00:47Z","timestamp":1729486847000},"page":"333-347","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":16,"title":["Targeting Sphingosine-1-Phosphate Signaling to Prevent the Progression of Aortic Valve Disease"],"prefix":"10.1161","volume":"151","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6107-7421","authenticated-orcid":true,"given":"Marcel","family":"Benkhoff","sequence":"first","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital D\u00fcsseldorf, Medical Faculty of the Heinrich Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany (M. Benkhoff, M. Barcik, P.M., J.D., P.K., M.H., T.H., S.Z., J.S., M.C., C.H., L.W., H.H., G.A.-K., D.M., J.W., L.D., C.Q., N.G., T.Z., M.K., A.P.)."},{"name":"Institute of Analytical Chemistry, University of Vienna, Vienna, Austria (M. Benkhoff, C.C., R.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maike","family":"Barcik","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital D\u00fcsseldorf, Medical Faculty of the Heinrich Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany (M. Benkhoff, M. Barcik, P.M., J.D., P.K., M.H., T.H., S.Z., J.S., M.C., C.H., L.W., H.H., G.A.-K., D.M., J.W., L.D., C.Q., N.G., T.Z., M.K., A.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5406-3937","authenticated-orcid":true,"given":"Philipp","family":"Mourikis","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital D\u00fcsseldorf, Medical Faculty of the Heinrich Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany (M. Benkhoff, M. Barcik, P.M., J.D., P.K., M.H., T.H., S.Z., J.S., M.C., C.H., L.W., H.H., G.A.-K., D.M., J.W., L.D., C.Q., N.G., T.Z., M.K., A.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana","family":"Dahlmanns","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital D\u00fcsseldorf, Medical Faculty of the Heinrich Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany (M. Benkhoff, M. Barcik, P.M., J.D., P.K., M.H., T.H., S.Z., J.S., M.C., C.H., L.W., H.H., G.A.-K., D.M., J.W., L.D., C.Q., N.G., T.Z., M.K., A.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paulina","family":"Kahmann","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital D\u00fcsseldorf, Medical Faculty of the Heinrich Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany (M. Benkhoff, M. Barcik, P.M., J.D., P.K., M.H., T.H., S.Z., J.S., M.C., C.H., L.W., H.H., G.A.-K., D.M., J.W., L.D., C.Q., N.G., T.Z., M.K., A.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"Wollnitzke","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine III, University Hospital D\u00fcsseldorf, Heinrich Heine University D\u00fcsseldorf, Germany (P.W., J.H., N.S., J.D.-J., B.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moritz","family":"Hering","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital D\u00fcsseldorf, Medical Faculty of the Heinrich Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany (M. Benkhoff, M. Barcik, P.M., J.D., P.K., M.H., T.H., S.Z., J.S., M.C., C.H., L.W., H.H., G.A.-K., D.M., J.W., L.D., C.Q., N.G., T.Z., M.K., A.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Huckenbeck","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital D\u00fcsseldorf, Medical Faculty of the Heinrich Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany (M. Benkhoff, M. Barcik, P.M., J.D., P.K., M.H., T.H., S.Z., J.S., M.C., C.H., L.W., H.H., G.A.-K., D.M., J.W., L.D., C.Q., N.G., T.Z., M.K., A.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Hoppe","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine III, University Hospital D\u00fcsseldorf, Heinrich Heine University D\u00fcsseldorf, Germany (P.W., J.H., N.S., J.D.-J., B.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Semleit","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine III, University Hospital D\u00fcsseldorf, Heinrich Heine University D\u00fcsseldorf, Germany (P.W., J.H., N.S., J.D.-J., B.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Deister-Jonas","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine III, University Hospital D\u00fcsseldorf, Heinrich Heine University D\u00fcsseldorf, Germany (P.W., J.H., N.S., J.D.-J., B.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saif","family":"Zako","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital D\u00fcsseldorf, Medical Faculty of the Heinrich Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany (M. Benkhoff, M. Barcik, P.M., J.D., P.K., M.H., T.H., S.Z., J.S., M.C., C.H., L.W., H.H., G.A.-K., D.M., J.W., L.D., C.Q., N.G., T.Z., M.K., A.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmin","family":"Seel","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital D\u00fcsseldorf, Medical Faculty of the Heinrich Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany (M. Benkhoff, M. Barcik, P.M., J.D., P.K., M.H., T.H., S.Z., J.S., M.C., C.H., L.W., H.H., G.A.-K., D.M., J.W., L.D., C.Q., N.G., T.Z., M.K., A.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Coman","sequence":"additional","affiliation":[{"name":"Institute of Analytical Chemistry, University of Vienna, Vienna, Austria (M. Benkhoff, C.C., R.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mareike","family":"Barth","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, University Hospital Aachen, RWTH Aachen University, Germany (M. Barth, P.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mareike","family":"Cramer","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital D\u00fcsseldorf, Medical Faculty of the Heinrich Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany (M. Benkhoff, M. Barcik, P.M., J.D., P.K., M.H., T.H., S.Z., J.S., M.C., C.H., L.W., H.H., G.A.-K., D.M., J.W., L.D., C.Q., N.G., T.Z., M.K., A.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8066-2239","authenticated-orcid":true,"given":"Carolin","family":"Helten","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital D\u00fcsseldorf, Medical Faculty of the Heinrich Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany (M. Benkhoff, M. Barcik, P.M., J.D., P.K., M.H., T.H., S.Z., J.S., M.C., C.H., L.W., H.H., G.A.-K., D.M., J.W., L.D., C.Q., N.G., T.Z., M.K., A.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Wildeis","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital D\u00fcsseldorf, Medical Faculty of the Heinrich Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany (M. Benkhoff, M. Barcik, P.M., J.D., P.K., M.H., T.H., S.Z., J.S., M.C., C.H., L.W., H.H., G.A.-K., D.M., J.W., L.D., C.Q., N.G., T.Z., M.K., A.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital D\u00fcsseldorf, Medical Faculty of the Heinrich Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany (M. Benkhoff, M. Barcik, P.M., J.D., P.K., M.H., T.H., S.Z., J.S., M.C., C.H., L.W., H.H., G.A.-K., D.M., J.W., L.D., C.Q., N.G., T.Z., M.K., A.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabrielle","family":"Al-Kassis","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital D\u00fcsseldorf, Medical Faculty of the Heinrich Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany (M. Benkhoff, M. Barcik, P.M., J.D., P.K., M.H., T.H., S.Z., J.S., M.C., C.H., L.W., H.H., G.A.-K., D.M., J.W., L.D., C.Q., N.G., T.Z., M.K., A.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Metzen","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital D\u00fcsseldorf, Medical Faculty of the Heinrich Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany (M. Benkhoff, M. Barcik, P.M., J.D., P.K., M.H., T.H., S.Z., J.S., M.C., C.H., L.W., H.H., G.A.-K., D.M., J.W., L.D., C.Q., N.G., T.Z., M.K., A.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Hesse","sequence":"additional","affiliation":[{"name":"Department of Molecular Cardiology, Heinrich Heine University D\u00fcsseldorf, Germany (J.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Weber","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital D\u00fcsseldorf, Medical Faculty of the Heinrich Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany (M. Benkhoff, M. Barcik, P.M., J.D., P.K., M.H., T.H., S.Z., J.S., M.C., C.H., L.W., H.H., G.A.-K., D.M., J.W., L.D., C.Q., N.G., T.Z., M.K., A.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Dannenberg","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital D\u00fcsseldorf, Medical Faculty of the Heinrich Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany (M. Benkhoff, M. Barcik, P.M., J.D., P.K., M.H., T.H., S.Z., J.S., M.C., C.H., L.W., H.H., G.A.-K., D.M., J.W., L.D., C.Q., N.G., T.Z., M.K., A.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Payam","family":"Akhyari","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, University Hospital Aachen, RWTH Aachen University, Germany (M. Barth, P.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Artur","family":"Lichtenberg","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, Medical Faculty and University Hospital D\u00fcsseldorf, Heinrich-Heine-University D\u00fcsseldorf, D\u00fcsseldorf, Germany (A.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Quast","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital D\u00fcsseldorf, Medical Faculty of the Heinrich Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany (M. Benkhoff, M. Barcik, P.M., J.D., P.K., M.H., T.H., S.Z., J.S., M.C., C.H., L.W., H.H., G.A.-K., D.M., J.W., L.D., C.Q., N.G., T.Z., M.K., A.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norbert","family":"Gerdes","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital D\u00fcsseldorf, Medical Faculty of the Heinrich Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany (M. Benkhoff, M. Barcik, P.M., J.D., P.K., M.H., T.H., S.Z., J.S., M.C., C.H., L.W., H.H., G.A.-K., D.M., J.W., L.D., C.Q., N.G., T.Z., M.K., A.P.)."},{"name":"Cardiovascular Research Institute D\u00fcsseldorf (CARID), D\u00fcsseldorf, Germany (N.G., M.K., A.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Zeus","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital D\u00fcsseldorf, Medical Faculty of the Heinrich Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany (M. Benkhoff, M. Barcik, P.M., J.D., P.K., M.H., T.H., S.Z., J.S., M.C., C.H., L.W., H.H., G.A.-K., D.M., J.W., L.D., C.Q., N.G., T.Z., M.K., A.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Borst","sequence":"additional","affiliation":[{"name":"DFG Heisenberg Group Cardiovascular Thromboinflammation and Translational Thrombocardiology, University of T\u00fcbingen, T\u00fcbingen, Germany (O.B.)."},{"name":"Department of Cardiology and Angiology, University of T\u00fcbingen, T\u00fcbingen, Germany (O.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malte","family":"Kelm","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital D\u00fcsseldorf, Medical Faculty of the Heinrich Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany (M. Benkhoff, M. Barcik, P.M., J.D., P.K., M.H., T.H., S.Z., J.S., M.C., C.H., L.W., H.H., G.A.-K., D.M., J.W., L.D., C.Q., N.G., T.Z., M.K., A.P.)."},{"name":"Cardiovascular Research Institute D\u00fcsseldorf (CARID), D\u00fcsseldorf, Germany (N.G., M.K., A.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Petzold","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charit\u00e9, Charit\u00e9 Universit\u00e4tsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany (T.P.)."},{"name":"DZHK (German Centre for Cardiovascular Research), Partner site Berlin, Germany (T.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Ahrends","sequence":"additional","affiliation":[{"name":"Institute of Analytical Chemistry, University of Vienna, Vienna, Austria (M. 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