Sphingosine-1-Phosphate Receptor Agonist Fingolimod Reduces Myocardial Ischemia-Reperfusion Injury and Apoptosis Increasing Long-Term Left Ventricular Function after Heart Transplantation

Abstract

Purpose Fingolimod, a sphingosine-1-phosphate receptor agonist, is approved for the treatment of multiple sclerosis and exerts antiapoptotic properties. We hypothesized that sphingosine-1-phosphate receptor activation with fingolimod in the donor hearts could protect against ischemia/reperfusion injury and preserve myocardial function in a heterotopic rat heart transplantation model. Methods Before explantation, donor Wistar rats received finfolimod (1 mg/kg iv, n= 40) or saline (control, n=40). The hearts were excised, stored in cold preservation solution for 1 hour and heterotopically transplanted. Left ventricular function of the graft and myocardial markers of apoptosis, nitro-oxidative stress, inflammation and fibrosis have been assessed after 24 hour (early phase) and 1 month (late phase) from transplantation. Results Fingolimod treatment activated the cardioprotective reperfusion injury salvage kinase Akt and extracellular receptor kinase 1/2 in the early phase after transplantation, leading to decreased cardiomyocyte apoptosis (TUNEL) and reduced myocardial nitro-oxidative stress (malondialdehyde, nitrotyrosine) and inflammation (CCL5/RANTES). In the late phase fingolimod decreased interstitial fibrosis and improved LV systolic and diastolic functions (pressure-volume analysis). Conclusion Sphingosine-1-phosphate receptor activation with fingolimod before heart transplantation activates anti-apoptotic and anti-inflammatory pathway reducing graft ischemia-reperfusion injury. This produces a reduced myocardial fibrosis and improved left ventricular function in a chronic phase. Fingolimod might represent a useful tool for cardioprotection in the clinical setting of heart transplantation surgery soon. Fingolimod, a sphingosine-1-phosphate receptor agonist, is approved for the treatment of multiple sclerosis and exerts antiapoptotic properties. We hypothesized that sphingosine-1-phosphate receptor activation with fingolimod in the donor hearts could protect against ischemia/reperfusion injury and preserve myocardial function in a heterotopic rat heart transplantation model. Before explantation, donor Wistar rats received finfolimod (1 mg/kg iv, n= 40) or saline (control, n=40). The hearts were excised, stored in cold preservation solution for 1 hour and heterotopically transplanted. Left ventricular function of the graft and myocardial markers of apoptosis, nitro-oxidative stress, inflammation and fibrosis have been assessed after 24 hour (early phase) and 1 month (late phase) from transplantation. Fingolimod treatment activated the cardioprotective reperfusion injury salvage kinase Akt and extracellular receptor kinase 1/2 in the early phase after transplantation, leading to decreased cardiomyocyte apoptosis (TUNEL) and reduced myocardial nitro-oxidative stress (malondialdehyde, nitrotyrosine) and inflammation (CCL5/RANTES). In the late phase fingolimod decreased interstitial fibrosis and improved LV systolic and diastolic functions (pressure-volume analysis). Sphingosine-1-phosphate receptor activation with fingolimod before heart transplantation activates anti-apoptotic and anti-inflammatory pathway reducing graft ischemia-reperfusion injury. This produces a reduced myocardial fibrosis and improved left ventricular function in a chronic phase. Fingolimod might represent a useful tool for cardioprotection in the clinical setting of heart transplantation surgery soon.