The Sphingosine 1-Phosphate Receptor Agonist Fingolimod Increases Myocardial Salvage and Decreases Adverse Post-Infarction Left Ventricular Remodeling in a Porcine Model of Ischemia-Reperfusion
Background—Fingolimod, a sphingosine-1 phosphate receptor (S1P-R) agonist, is used for the treatment of multiple sclerosis and it also exerts antiapoptotic properties. We hypothesized that S1P-R activation with fingolimod during acute myocardial infarction (MI) inhibits apoptosis leading to increased myocardial salvage, reduced infarct size, and mitigated left ventricular (LV) remodeling in a porcine model of ischemia-reperfusion.
Methods and Results—Ischemia-reperfusion was induced in pigs by balloon occlusion of the LAD, followed by reperfusion. Animals randomly received fingolimod or saline (control). In acute experiments, fingolimod treatment activated the cardioprotective RISK and SAFE pathways in the infarct border zone 24 hours post-MI leading to decreased cardiomyocyte apoptosis and reduced myocardial oxidative stress. These effects were abolished by specific inhibitors of both pathways demonstrating that fingolimod-induced cardioprotection was mediated by RISK and SAFE. In chronic experiments, fingolimod significantly improved myocardial salvage, reduced infarct size and improved systolic LV function measured by cardiac magnetic resonance, one week and one month post-MI. Importantly, fingolimod mitigated the development of adverse post-MI LV remodeling one month post-MI. Specifically, fingolimod treatment led to a significant reduction in LV mass, LV dilatation, and neurohormonal activation, and it preserved LV geometry. Further, fingolimod decreased interstitial fibrosis, cardiomyocyte hypertrophy, and chronic activation of Akt and ERK1/2 in the remote non-infarcted myocardium.
Conclusions—S1P-R activation with fingolimod during acute MI reduced infarct size via the RISK and SAFE pathways, improved systolic LV function, and mitigated post-MI LV remodeling. Our data strongly support a cardioprotective role for S1P-R activation during MI.
- myocardial infarction
- ischemia reperfusion injury
- left ventricular remodeling
- animal model cardiovascular disease
- Received July 6, 2015.
- Revision received November 20, 2015.
- Accepted January 8, 2016.