AUTHOR=Ahmed Naseer , Mehmood Adeela , Linardi Daniele , Sadiq Soban , Tessari Maddalena , Meo Sultan Ayoub , Rehman Rehana , Hajjar Waseem M. , Muhammad Nazeer , Iqbal Muhammad Perwaiz , Gilani Anwar-ul-Hassan , Faggian Giuseppe , Rungatscher Alessio 

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

JOURNAL=Frontiers in Pharmacology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2019.00802

DOI=10.3389/fphar.2019.00802

ISSN=1663-9812

ABSTRACT=<p><bold>Objective:</bold> 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.</p><p><bold>Methods:</bold> 30 Sprague–Dawley rats (300–350 g) were randomized into two groups: Group-A, treated with FTY720 1 mg/kg <italic>via</italic> 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.</p><p><bold>Results:</bold> 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.</p><p><bold>Conclusion:</bold> 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.</p>