Duse, Dragos AndreiSchroeder, Nathalie HanneloreSrivastava, TanuBenkhoff, MarcelVogt, JensNowak, Melissa KimFunk, FlorianSemleit, NinaWollnitzke, PhilippErkens, RalfKoetter, SebastianMeuth, Sven GuentherKeul, PetraSantos, WebsterPolzin, AminKelm, MalteKrueger, MartinaSchmitt, JoachimLevkau, Bodo2025-11-052025-11-052024-10-010300-8428https://hdl.handle.net/10919/138857The 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 similar to 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.application/pdfenCreative Commons Attribution 4.0 InternationalSphingosine-1-phosphateLeft-ventricular remodelingCardioprotectionMfsd2bArticle - Refereedhttps://doi.org/10.1007/s00395-024-01073-x1195391101731435-1803