Abstract 552: The Immunosuppressant FTY720 Increases Longevity and Prevents Chronic Heart Failure in HypoE Mice Deficient in the SR-BI Receptor that Survive Myocardial Infarction Caused by Diet-induced Coronary Atherosclerosis
FTY720 is an analogue of sphingosine-1-phosphate, which is cardioprotective during acute injury. Whether FTY720 affords cardioprotection and prevents chronic heart failure (CHF) after myocardial infarction (MI) is unknown. Initially we added FTY720 (0.3mg/kg/day) to the drinking water of C57BL/6J mice. After ex vivo cardiac I/R injury these mice had significantly improved left ventricular (LV) developed pressure and reduced infarct size compared with controls. Next, we fed FTY720 to a previously described mouse model of diet-induced coronary atherosclerosis, MI and premature death. This model was developed by breeding our hypomorphic apoE mice, also referred to as “HypoE” mice, which express sub-physiological apoE in all tissues due to Apoeh/h alleles, to mice deficient in the SR-BI receptor (Apoeh/h/SRB1-/- mice). These mice were given a high fat diet (HFD) for 4 weeks and treated or not with oral FTY720 (0.05mg/kg/day). This therapy sharply reduced mortality (p<0.02) and resulted in better LV function and less LV remodeling compared with controls without reducing hypercholesterolemia or atherosclerosis. Rather, FTY720 produced immunosuppression by reducing T and B cells and increasing the percentage of CD4+Foxp3+ regulatory T cells (Tregs) in the circulation, spleen and lymph nodes. Importantly, FTY720-treated mice exhibited increased TGF-β and reduced IFN-γ expression in the heart. Cardiac expression of CD4 was increased and correlated with molecules involved in natural Treg activity including TGF-β and GITR. Lastly, Apoeh/h/SRB1-/- mice were bred to Mx1-Cre mice. Apoeh/h/SRB1-/-Mx1-Cre mice were given HFD for 3.5 weeks and hyperlipidemia was reversed by inducible Cre mediated gene repair of the HypoE allele using pIpC injections. The mice were then treated or not with oral FTY720 (0.05mg/kg/day). Fifteen weeks after lipid lowering, sham-treated mice had developed profound CHF while in mice receiving FTY720 cardiac function returned to normal. We conclude that long-term FTY720-treatment enhances LV function and increases longevity in mice with CHF and prevents CHF in mice that survive MI. These benefits resulted not from atheroprotection but from profound systemic immunosuppression resulting in reduced cardiac inflammation.
- © 2013 by American Heart Association, Inc.