Fingolimod (FTY720) Preserves High Energy Phosphates and Improves Cardiac Function in Heterotopic Heart Transplantation Model.

Naseer Ahmed,Javeria Farooq,Alessio Rungatscher,Azam Jan,Soban Sadiq,Sultan Ayoub Meo,Giuseppe Faggian,Faisal H Cheema

doi:10.3390/ijms21186548

Abstract

During heart transplantation, donor heart leads to reduced oxygen supply resulting in low level of high energy phosphate (HEP) reserves in cardiomyocyte. Lower HEP is one of the underlying reasons of cell death due to ischemia. In this study we investigated the role of Fingolimod (FTY720) in heart transplantation ischemia. Eight groups of Sprague-Dawley rats (n = 5 for each subgroup) were made, A1 and C1 were given FTY720 1 mg/kg while B1 and D1 were given normal saline. The hearts were implanted into another set of similar rats after preservation period of 1 h at 4–8 °C. Significantly higher Left ventricular systolic pressure (LVSP), dP/dT maximum (p < 0.05), dP/dT minimum (p < 0.05) were recorded in the FTY720 treated group after 24 h of reperfusion while after 1 h of reperfusion, there were no significant differences in LVSP, maximum and negative dP/dT, and Left ventricular end diastolic pressure (LVEDP) between the control and the FTY720-treated transplant groups. Coronary blood flow (CBF) was enhanced (p < 0.05) in the FTY720 treated group after 1 and 24 h. ATP p < 0.001, p < 0.05 at 1 and 24 h, ADP p < 0.001, p > 0.05 at 1 and 24 h, and phosphocreatine p < 0.05, p > 0.05 at 1 and 24 h were better preserved by FTY720 treatment as compared to control group. The study concluded that pretreatment of grafted hearts with FTY720 improved hemodynamics, CBF, high energy phosphate reserves, reduces the peroxynitrite level and poly (ADP ribose) polymerase (PARP) inhibition that prevents ischemia-reperfusion injury.

Highlights

Heart failure (HF) is the leading complication of many cardiovascular diseases [1,2]
The purpose of the present study was to explore the effects of FTY720 on hemodynamic parameters, coronary blood flow, reservation of high energy phosphates, and peroxynitrite expression
Systolic cardiac function graphs showed a major shift in the FTY720 treated group in comparison to the control-saline treated group

Summary

Introduction

Heart failure (HF) is the leading complication of many cardiovascular diseases [1,2]. During ischemia, compromised blood supply results in decrease supply of oxygen and low level of glucose that leads to the utilization of glycogen and initiation of anaerobic glycolysis. Levels of ATP, glycogen, and creatinine phosphate remain closely related in an ischemic myocardium [4]. Depletion of high energy phosphates is linked with harmful injury in acutely ischemic myocardium. It is observed that more than 90% of the ATP gets depleted after 40 min of ischemia and is related with major modifications in cell structure [5]. Presence of peroxynitrite exacerbates myocardial damage during ischemic reperfusion injury. Peroxynitrite stimulates nuclear enzyme PARP, that can lead to impaired cardiovascular functions and inflammatory disorders [6]

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