Targeting Sphingosine-1-Phosphate Signaling to Prevent the Progression of Aortic Valve Disease
Abstract
BACKGROUND: 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. METHODS: AVD progression and its consequences for cardiac function were examined in a murine wire injury–induced 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. RESULTS: 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 GSK3β-Wnt-β-catenin pathway. In patients with AVD, stenotic valves exposed to high wall shear stress had higher S1P content and increased SphK1 expression. CONCLUSIONS: 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.
Article Details
Authors (35)
Marcel Benkhoff
Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, 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.).
Maike Barcik
Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, 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.).
Philipp Mourikis
Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, 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.).
Jana Dahlmanns
Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, 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.).
Paulina Kahmann
Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, 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.).
Philipp Wollnitzke
Institute of Molecular Medicine III, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany (P.W., J.H., N.S., J.D.-J., B.L.).
Moritz Hering
Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, 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.).
Tim Huckenbeck
Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, 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.).
Julia Hoppe
Institute of Molecular Medicine III, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany (P.W., J.H., N.S., J.D.-J., B.L.).
Nina Semleit
Institute of Molecular Medicine III, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany (P.W., J.H., N.S., J.D.-J., B.L.).
Jennifer Deister-Jonas
Institute of Molecular Medicine III, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany (P.W., J.H., N.S., J.D.-J., B.L.).
Saif Zako
Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, 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.).
Jasmin Seel
Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, 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.).
Cristina Coman
Institute of Analytical Chemistry, University of Vienna, Vienna, Austria (M. Benkhoff, C.C., R.A.).
Mareike Barth
Mareike Cramer
Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, 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.).
Carolin Helten
Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, 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.).
Laura Wildeis
Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, 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.).
Hao Hu
Gabrielle Al-Kassis
Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, 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.).
Daniel Metzen
Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, 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.).
Julia Hesse
Jessica Weber
Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, 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.).
Lisa Dannenberg
Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, 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.).
Payam Akhyari
Artur Lichtenberg
Christine Quast
Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, 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.).
Norbert Gerdes
Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, 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.).
Tobias Zeus
Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, 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.).
Oliver Borst
Malte Kelm
Tobias Petzold
Department of Cardiology, Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charité, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany (T.P.).
Robert Ahrends
Institute of Analytical Chemistry, University of Vienna, Vienna, Austria (M. Benkhoff, C.C., R.A.).
Bodo Levkau
Institute of Molecular Medicine III, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany (P.W., J.H., N.S., J.D.-J., B.L.).
Amin Polzin
University Hospital Düsseldorf, Düsseldorf, Germany