Dokument: Deficiency of the sphingosine-1-phosphate (S1P) transporter Mfsd2b protects the heart against hypertension-induced cardiac remodeling by suppressing the L-type-Ca2+ channel
| Titel: | Deficiency of the sphingosine-1-phosphate (S1P) transporter Mfsd2b protects the heart against hypertension-induced cardiac remodeling by suppressing the L-type-Ca2+ channel | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=67845 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20241203-112913-5 | |||||||
| Kollektion: | Publikationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Texte » Artikel, Aufsatz | |||||||
| Medientyp: | Text | |||||||
| Autoren: | Duse, Dragos Andrei [Autor] Schröder, Nathalie H. [Autor] Srivastava, Tanu [Autor] Benkhoff, Marcel [Autor] Vogt, Jens [Autor] Nowak, Melissa K. [Autor] Funk, Florian [Autor] Semleit, Nina [Autor] Wollnitzke, Philipp [Autor] Erkens, Ralf [Autor] | |||||||
| Dateien: |
| |||||||
| Stichwörter: | Left-ventricular remodeling, Mfsd2b,Sphingosine-1-phosphate, Cardioprotection | |||||||
| Beschreibung: | The erythrocyte S1P transporter Mfsd2b is also expressed in the heart. We hypothesized that S1P transport by Mfsd2b is involved in cardiac function. Hypertension-induced cardiac remodeling was induced by 4-weeks Angiotensin II (AngII) administration and assessed by echocardiography. Ca2+ transients and sarcomere shortening were examined in adult cardiomyocytes (ACM) from Mfsd2b+/+ and Mfsd2b−/− mice. Tension and force development were measured in skinned cardiac fibers. Myocardial gene expression was determined by real-time PCR, Protein Phosphatase 2A (PP2A) by enzymatic assay, and S1P by LC/MS, respectively. Msfd2b was expressed in the murine and human heart, and its deficiency led to higher cardiac S1P. Mfsd2b−/− mice had regular basal cardiac function but were protected against AngII-induced deterioration of left-ventricular function as evidenced by ~ 30% better stroke volume and cardiac index, and preserved ejection fraction despite similar increases in blood pressure. Mfsd2b−/− ACM exhibited attenuated Ca2+ mobilization in response to isoprenaline whereas contractility was unchanged. Mfsd2b−/− ACM showed no changes in proteins responsible for Ca2+ homeostasis, and skinned cardiac fibers exhibited reduced passive tension generation with preserved contractility. Verapamil abolished the differences in Ca2+ mobilization between Mfsd2b+/+ and Mfsd2b−/− ACM suggesting that S1P inhibits L-type-Ca2+ channels (LTCC). In agreement, intracellular S1P activated the inhibitory LTCC phosphatase PP2A in ACM and PP2A activity was increased in Mfsd2b−/− hearts. We suggest that myocardial S1P protects from hypertension-induced left-ventricular remodeling by inhibiting LTCC through PP2A activation. Pharmacologic inhibition of Mfsd2b may thus offer a novel approach to heart failure. | |||||||
| Rechtliche Vermerke: | Originalveröffentlichung:
Duşe, D. A., Schröder, N. H., Srivastava, T., Benkhoff, M., Vogt, J., Nowak, M. K., Funk, F., Semleit, N., Wollnitzke, P., Erkens, R., Kötter, S., Meuth, S., Keul, P., Santos, W., Polzin, A., Kelm, M., Krüger, M., Schmitt, J. P., & Levkau, B. (2024). Deficiency of the sphingosine-1-phosphate (S1P) transporter Mfsd2b protects the heart against hypertension-induced cardiac remodeling by suppressing the L-type-Ca2+ channel. Basic Research in Cardiology, 119(5), 853–868. https://doi.org/10.1007/s00395-024-01073-x | |||||||
| Lizenz: |  Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz | |||||||
| Fachbereich / Einrichtung: | Medizinische Fakultät | |||||||
| Dokument erstellt am: | 03.12.2024 | |||||||
| Dateien geändert am: | 03.12.2024 |
