Cardioprotective Effects of Sphingosine-1-Phosphate Receptor Immunomodulator FTY720 in a Clinically Relevant Model of Cardioplegic Arrest and Cardiopulmonary Bypass

Objective: FTY720, an immunomodulator derived from sphingosine-1-phosphate,

has recently demonstrated its immunomodulatory, anti-inflammatory, anti-oxidant,

anti-apoptotic and anti-inflammatory properties. Furthermore, FTY720 might be a key

pharmacological target for preconditioning. In this preclinical model, we have investigated

the effects of FTY720 on myocardium during reperfusion in an experimental model of

cardioplegic arrest (CPA) and cardiopulmonary bypass.

Methods: 30 Sprague–Dawley rats (300–350 g) were randomized into two groups:

Group-A, treated with FTY720 1 mg/kg via intravenous cannulation, and Group-B, as

control. After 15 min of treatment, rats underwent CPA for 30 min followed by initiation

of extracorporeal life support for 2 h. Support weaning was done, and blood and

myocardial tissues were collected for analysis. Hemodynamic parameters, inflammatory

mediators, nitro-oxidative stress, neutrophil infiltration, immunoblotting analysis, and

immunohistochemical staining were analyzed and compared between groups.

Results: FTY720 treatment activated the Akt/Erk1/2 signaling pathways, reduced

the level of inflammatory mediators, activated antiapoptotic proteins, and inhibited

proapoptotic proteins, leading to reduced nitro-oxidative stress and cardiomyocyte

apoptosis. Moreover, significant preservation of high-energy phosphates were observed

in the FTY720-treated group. This resulted in improved recovery of left ventricular systolic

and diastolic functions.

Conclusion: The cardioprotective mechanism in CPA is associated with activation of

prosurvival cell signaling pathways that prevents myocardial damage. FTY720 preserves

high-energy phosphates attenuates myocardial inflammation and oxidative stress, and

improves cardiac function.