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

• Published in: International journal of molecular sciences Vol. 21; no. 18; p. 6548
• Main Authors: Ahmed, Naseer, Farooq, Javeria, Sadiq, Soban, Meo, Sultan Ayoub, Jan, Azam, Cheema, Faisal H, Faggian, Giuseppe, Rungatscher, Alessio
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 08-09-2020; MDPI
• Subjects: Animals; Apoptosis; Blood flow; Blood pressure; Cardiac function; Cardiomyocytes; Cell death; Cerebral blood flow; Coronary Artery Disease - drug therapy; Coronary Artery Disease - physiopathology; coronary blood flow; Coronary Circulation - drug effects; Diastolic pressure; Energy; fingolimod (FTY720); Fingolimod Hydrochloride - metabolism; Fingolimod Hydrochloride - pharmacology; FTY720; Heart - drug effects; Heart - physiopathology; Heart failure; Heart Transplantation - methods; Hemodynamics; high energy phosphates; Injury prevention; Ischemia; Low level; Metabolism; Metabolites; Myocardial Ischemia - physiopathology; Myocardial Reperfusion Injury - physiopathology; Nitric oxide; Oxidative stress; Peroxynitrite; Phosphates; Phosphocreatine; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerases - metabolism; Preservation; Pretreatment; Rats; Rats, Sprague-Dawley; Reperfusion; Ribose; Subgroups; Systolic pressure; Transplantation; Transplants & implants; Ventricle; fingolimod (FTY720); poly (ADP ribose) polymerase; cardiac function; coronary blood flow; high energy phosphates
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21186548

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 (
= 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 (
< 0.05), dP/dT minimum (
< 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 (
< 0.05) in the FTY720 treated group after 1 and 24 h. ATP
< 0.001,
< 0.05 at 1 and 24 h, ADP
< 0.001,
> 0.05 at 1 and 24 h, and phosphocreatine
< 0.05,
> 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.