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

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.

FTY720-P, a Biased S1PR Ligand, Increases Mitochondrial Function through STAT3 Activation in Cardiac Cells

“…Nanomolar blood FTY720-P concentrations provide protection against inflammation and heart disease in mice [ 38 ]. In addition, FTY720-P improves glucose metabolism in mice made obese with a high-fat diet [ 41 ].…”

“…FTY720-P is a S1PR ligand that decreases inflammation and promotes survival and metabolic activation [ 12 , 38 , 41 , 48 ]. This compound induces the activation of several pro-survival signals, associated with a protective effect in tissues such as the brain and heart [ 7 , 49 ].…”

“…Another report shows that bone-marrow-derived dendritic cells co-incubated with LPS and FTY720-P increase mitochondrial mass as compared with LPS-treated cells [ 40 ]. Moreover, FTY720-P can stabilize ATP and creatine levels in a heterotopic model of heart transplantation [ 38 ]. Altogether, these data suggest a close link between FTY720-P signaling and mitochondrial function.…”

“…Although the basis of such distinct results is unknown, it might be related to tissue-specific patterns or to the FTY720 concentration used in different studies. Noteworthy, recent data evidenced that FTY720-P administration can sustain ATP and creatine levels in hearts, reduce mitochondrial ROS production in menadione-treated neurons, and increase the mitochondrial mass of bone-marrow-derived dendritic cells when co-incubated with LPS [ 38 , 39 , 40 ].…”

Protecting the Mitochondria in Cardiac Disease

“…However, during this procedure, the temporary reduction in oxygen supply dampens high-energy phosphate (HEP) reserves in cardiomyocytes and elicits cell death due to the ischaemic state. As such, Ahmed and colleagues [ 24 ] investigated whether pre-treated hearts with the immunosuppressant fingolimod (FTY720) could demonstrate better cardiac performance following transplantation. Interestingly, FTY720 pre-treatment was shown to improve hemodynamics, coronary blood flow, and HEP reserves in heterotopic transplanted hearts, with accompanying reductions in peroxynitrite levels and caspase activity, which may imply a decrease in cell death following IR.…”