Deficiency of the sphingosine-1-phosphate (S1P) transporter Mfsd2b protects the heart against hypertension-induced cardiac remodeling by suppressing the L-type-Ca 2+ channel.

Autor: Duse DA; Institute for Molecular Medicine III, University Hospital Düsseldorf and Heinrich Heine University, Düsseldorf, Germany.; Department of Cardiology, Pneumology, and Vascular Medicine, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.; Cardiovascular Research Institute Düsseldorf (CARID), Düsseldorf, Germany., Schröder NH; Institute for Molecular Medicine III, University Hospital Düsseldorf and Heinrich Heine University, Düsseldorf, Germany., Srivastava T; Institute of Pharmacology, University Hospital Düsseldorf, Düsseldorf, Germany., Benkhoff M; Department of Cardiology, Pneumology, and Vascular Medicine, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany., Vogt J; Institute for Molecular Medicine III, University Hospital Düsseldorf and Heinrich Heine University, Düsseldorf, Germany., Nowak MK; Institute for Molecular Medicine III, University Hospital Düsseldorf and Heinrich Heine University, Düsseldorf, Germany., Funk F; Institute of Pharmacology, University Hospital Düsseldorf, Düsseldorf, Germany., Semleit N; Institute for Molecular Medicine III, University Hospital Düsseldorf and Heinrich Heine University, Düsseldorf, Germany., Wollnitzke P; Institute for Molecular Medicine III, University Hospital Düsseldorf and Heinrich Heine University, Düsseldorf, Germany., Erkens R; Department of Cardiology, Pneumology, and Vascular Medicine, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.; Cardiovascular Research Institute Düsseldorf (CARID), Düsseldorf, Germany., Kötter S; Institute of Cardiovascular Physiology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany., Meuth SG; Department of Neurology, Medical Faculty, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany., Keul P; Institute for Molecular Medicine III, University Hospital Düsseldorf and Heinrich Heine University, Düsseldorf, Germany., Santos W; Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA, 24060, USA., Polzin A; Department of Cardiology, Pneumology, and Vascular Medicine, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.; Cardiovascular Research Institute Düsseldorf (CARID), Düsseldorf, Germany., Kelm M; Department of Cardiology, Pneumology, and Vascular Medicine, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.; Cardiovascular Research Institute Düsseldorf (CARID), Düsseldorf, Germany., Krüger M; Cardiovascular Research Institute Düsseldorf (CARID), Düsseldorf, Germany.; Institute of Cardiovascular Physiology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany., Schmitt J; Cardiovascular Research Institute Düsseldorf (CARID), Düsseldorf, Germany.; Institute of Pharmacology, University Hospital Düsseldorf, Düsseldorf, Germany., Levkau B; Institute for Molecular Medicine III, University Hospital Düsseldorf and Heinrich Heine University, Düsseldorf, Germany. bodo.levkau@med.uni-duesseldorf.de.; Cardiovascular Research Institute Düsseldorf (CARID), Düsseldorf, Germany. bodo.levkau@med.uni-duesseldorf.de.
Jazyk: angličtina
Zdroj: Basic research in cardiology [Basic Res Cardiol] 2024 Oct; Vol. 119 (5), pp. 853-868. Date of Electronic Publication: 2024 Aug 07.
DOI: 10.1007/s00395-024-01073-x
Abstrakt: 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 2+ 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 Ca 2+ mobilization in response to isoprenaline whereas contractility was unchanged. Mfsd2b -/- ACM showed no changes in proteins responsible for Ca 2+ homeostasis, and skinned cardiac fibers exhibited reduced passive tension generation with preserved contractility. Verapamil abolished the differences in Ca 2+ mobilization between Mfsd2b +/+ and Mfsd2b -/- ACM suggesting that S1P inhibits L-type-Ca 2+ 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
Externí odkaz: