FTY720, an analogue of sphingosine-1-phosphate, is cardioprotective during acute injury. Whether long-term FTY720 affords cardioprotection is unknown. Here, we report the effects of oral FTY720 on ischemia/reperfusion injury and in hypomorphic apoE mice deficient in SR-BI receptor expression (ApoeR61h/h/SRB1−/− mice), a model of diet-induced coronary atherosclerosis and heart failure. We added FTY720 (0.3 mg·kg−1·d−1) to the drinking water of C57BL/6J mice. After ex vivo cardiac ischemia/reperfusion injury, these mice had significantly improved left ventricular (LV) developed pressure and reduced infarct size compared with controls. Subsequently, ApoeR61h/h/SRB1−/− mice fed a high-fat diet for 4 weeks were treated or not with oral FTY720 (0.05 mg·kg−1·d−1). This sharply reduced mortality (P < 0.02) and resulted in better LV function and less LV remodeling compared with controls without reducing hypercholesterolemia and atherosclerosis. Oral FTY720 reduced the number of blood lymphocytes and increased the percentage of CD4+Foxp3+ regulatory T cells (Tregs) in the circulation, spleen, and lymph nodes. FTY720-treated mice exhibited increased TGF-β and reduced IFN-γ expression in the heart. Also, CD4 expression was increased and strongly correlated with molecules involved in natural Treg activity, such as TGF-β and GITR. Our data suggest that long-term FTY720 treatment enhances LV function and increases longevity in mice with heart failure. These benefits resulted not from atheroprotection but from systemic immunosuppression and a moderate reduction of inflammation in the heart.
*Department of Medicine, University of California San Francisco, San Francisco, CA;
†University of California, San Francisco, CA;
‡Surgical Service, VA Medical Center, San Francisco, CA; and
§Department of Surgery, University of California, San Francisco, CA.
Reprints: Robert L. Raffai, PhD, Surgical Service, VA Medical Center, and Department of Surgery, University of California, 4150 Clement St, San Francisco, CA 94121 (e-mail: email@example.com).
Supported by grants from the National Institutes of Health HL089871 (RLR) and HL090606 (JSK), which were administered by the Northern California Institute for Research and Education, and a Merit Review grant from the Department of Veterans Affairs 5I01BX000532 to RLR, and with resources of the Veterans Affairs Medical Center, San Francisco, CA.
G. Wang and R. Y. Kim contributed equally to this study.
The authors report no conflicts of interest.
Received August 15, 2013
Accepted October 04, 2013