Introduction: Sphingosine-1-phosphate (S1P) is a cardioprotective bioactive lipid, the plasma levels of which are associated with the prevalence and severity of coronary artery disease, myocardial infarction, and ischemic cardiomyopathy. Major facilitator superfamily transporter 2b (MFSD2B) has been recently identified as S1P transporter in erythropoietic cells. However, we have found MFSD2B to be expressed in the murine heart and hypothesized that it might play a role in cardiac function.

Methods: Adult cardiomyocytes (ACM) were isolated from global Mfsd2b^+/+ and Mfsd2b^-/- mice; Ca²⁺_i transients and sarcomere shortening were examined in single ACM. S1P levels were evaluated by LC/MS. Echocardiography was performed before and after 4-week treatment with angiotensin II (AngII) monitored by serial blood pressure measurements using a tail-cuff system. Fibrosis was evaluated histomorphometrically after Sirius Red staining, and gene expression was assessed by real-time PCR. 

Results: Isolated ACM from Mfsd2b^-/- featuring four-fold higher S1P concentrations exhibited an impaired Ca²⁺ response to isoprenaline despite preserved contractility. The defect was abolished by verapamil administration. In vivo, left-ventricular functional and morphological parameters of Mfsd2b^-/- mice were similar to wild-type littermates. However, Mfsd2b^-/- were protected against AngII-induced cardiac hypertrophy and deterioration of cardiac function (stroke volume (±SD): 22.6±9 µL in wt vs. 32.7±9.6 µL in ko, p=0.0359; ejection fraction (±SD): 30.5±14% in wt vs. 42±5.8% in ko, p=0.0462) despite similar increases in blood pressure as measured by echocardiography, histomorphometric fibrosis evaluation and expression of embryonal genes such as atrial or B-type natriuretic peptides (ANP, BNP) and β-myosin heavy chain (β-MHC).

Conclusion: Our data suggest that myocardial S1P protects from pressure overload-induced heart failure. This may occur through regulation of the local Ca²⁺-response, perhaps through direct S1P effects on cardiomyocyte L-type-Ca²⁺-channels. Selective inhibition of the cardiac MFSD2B transporter may offer a new approach to heart failure.