Sphingosine-1-Phosphate Receptor Agonist, FTY720, Restores Coronary Flow Reserve in Diabetic Rats

Abstract

Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp vasomotor function. 12-14 By using PET with 13 N-ammonia, it is possible to measure myocardial perfusion in a non-invasive way and quantify myocardial blood flow (MBF) in a resting and pharmacologic stress phase with adenosine or dipyridamole (hyperemic response). 15 The use of 13 N-ammonia for quantification of MBF has been compromised by the non-linear relationship between tracer tissue retention and myocardial blood flow, and is suitable for the characterization of the status of coronary arteries and measuring the coronary perfusion reserve non-invasively.The purpose of the present study was to determine whether impaired coronary microvascular function in diabetic rats could be improved by the long-term administration of FTY720. We used the 13 NH3 MicroPET technique for detecting myocardial function in vivo to investigate the impact of CFR in the early stage of diabetes. oronary flow reserve (CFR) is a measure of the coronary vascular functionality and could be an important functional parameter to understand the pathophysiology of coronary microcirculation. 1 Impairment of CFR has been generally demonstrated in diabetic patients and animals with microvascular complications but without obvious obstructive coronary atherosclerosis. 2,3 Impaired CFR has been shown to confer great prognostic information for hard cardiovascular outcome, including all-cause mortality, cardiovascular death and non-fatal myocardial infarction. 4,5 FTY720, as a synthesized Sphingosine-1-phosphate (S1P) receptor agonist, can lower the inflammation reaction and promote lymph cell homing, 6,7 and has an important cardioprotective effect. Recently, it has been found that FTY720 has an important protect effect for diabetic microvessels and macrovessels. 8-11 To date, no study has found an improvement in CFR due to long-term FTY720 administration.Positron emission tomography (PET) is one of the few noninvasive methods available to quantitatively evaluate coronary There have been few studies investigating CFR in cases of relatively well-controlled therapy. The purpose of this study is to evaluate the effect of treatment with a Sphingosine-1-phosphate (S1P) receptor potent agonist, FTY720, on early diabetic rats in terms of CFR.

Implication of sphingosin-1-phosphate in cardiovascular regulation

“…S1P agonists FTY720 and KRP-203 dramatically attenuate the development of atherosclerosis in ApoE KO mice and LDL receptor KO mice (97). FTY720 has also been shown to improve the coronary dysfunction and restore the reduced coronary flow reserve in diabetic rats (100). …”

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

“…According to literature, S1P receptor agonists have an important role in immune suppression (Luessi et al, 2015). Various experimental models have been used to test for including a porcine model of I/R (Santos-Gallego et al, 2016) and spontaneous obstructive coronary atherosclerosis murine model (Xu et al, 2014). Using these models, a reduction in infarct size and low mortality have been shown in the FTY720-treated groups.…”

Fingolimod Plays Role in Attenuation of Myocardial Injury Related to Experimental Model of Cardiac Arrest and Extracorporeal Life Support Resuscitation

“…S1P receptor agonists have important roles in immune suppression [39]. A porcine model of I/R [17] and a spontaneous obstructive coronary atherosclerosis murine model [40] tested for immunosuppression, showed reduction in infarct size and mortality in the fingolimod-treated group. In the present study, a significantly lower concentration of pro-inflammatory cytokines was found in blood and tissues subjected to inflammation, a finding concordant with the previous data [40].…”