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Anstalt \u00f6ffentlichen Rechts"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Basic Res Cardiol"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>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. Ca<jats:sup>2+<\/jats:sup> transients and sarcomere shortening were examined in adult cardiomyocytes (ACM) from Mfsd2b<jats:sup>+\/+<\/jats:sup> and Mfsd2b<jats:sup>\u2212\/\u2212<\/jats:sup> 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<jats:sup>\u2212\/\u2212<\/jats:sup> mice had regular basal cardiac function but were protected against AngII-induced deterioration of left-ventricular function as evidenced by\u2009~\u200930% better stroke volume and cardiac index, and preserved ejection fraction despite similar increases in blood pressure. Mfsd2b<jats:sup>\u2212\/\u2212<\/jats:sup> ACM exhibited attenuated Ca<jats:sup>2+<\/jats:sup> mobilization in response to isoprenaline whereas contractility was unchanged. Mfsd2b<jats:sup>\u2212\/\u2212<\/jats:sup> ACM showed no changes in proteins responsible for Ca<jats:sup>2+<\/jats:sup> homeostasis, and skinned cardiac fibers exhibited reduced passive tension generation with preserved contractility. Verapamil abolished the differences in Ca<jats:sup>2+<\/jats:sup> mobilization between Mfsd2b<jats:sup>+\/+<\/jats:sup> and Mfsd2b<jats:sup>\u2212\/\u2212<\/jats:sup> ACM suggesting that S1P inhibits L-type-Ca<jats:sup>2+<\/jats:sup> channels (LTCC). In agreement, intracellular S1P activated the inhibitory LTCC phosphatase PP2A in ACM and PP2A activity was increased in Mfsd2b<jats:sup>\u2212\/\u2212<\/jats:sup> 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.<\/jats:p>","DOI":"10.1007\/s00395-024-01073-x","type":"journal-article","created":{"date-parts":[[2024,8,7]],"date-time":"2024-08-07T05:03:14Z","timestamp":1723006994000},"page":"853-868","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Deficiency of the sphingosine-1-phosphate (S1P) transporter Mfsd2b protects the heart against hypertension-induced cardiac remodeling by suppressing the L-type-Ca2+ channel"],"prefix":"10.1007","volume":"119","author":[{"given":"Dragos Andrei","family":"Duse","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie Hannelore","family":"Schr\u00f6der","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanu","family":"Srivastava","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel","family":"Benkhoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens","family":"Vogt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa Kim","family":"Nowak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Funk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Semleit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"Wollnitzke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Erkens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"K\u00f6tter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven G\u00fcnther","family":"Meuth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Keul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Webster","family":"Santos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amin","family":"Polzin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malte","family":"Kelm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Kr\u00fcger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim","family":"Schmitt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bodo","family":"Levkau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,8,7]]},"reference":[{"key":"1073_CR1","doi-asserted-by":"publisher","first-page":"8137","DOI":"10.1074\/jbc.273.14.8137","volume":"273","author":"GM Bokoch","year":"1998","unstructured":"Bokoch GM, Reilly AM, Daniels RH, King CC, Olivera A, Spiegel S, Knaus UG (1998) A GTPase-independent mechanism of p21-activated kinase activation. 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