The Effect And The Mechanism Of S1P2/3 Receptor To The Sudden Cardiac Death Induced By Heart Ischemia Reperfusion Injury

Objective1. To observe the effect of S1PR2/3 on heart and death rate during myocardial ischemia-reperfusion(I/R) in rats.2. To observe the effect of S1PR2/3 pretreated with C x43 uncoupler(heptanol) on heart and death rate during myocardial IR in rats.Methods1. Healthy adult male Sprague-Dawley rats were randomly divided into 7 groups: sham group, control group, IR control group, DMSO group, S1PR3 agonist group, S1PR3 antagonist group, S1PR2/3 antagonist group. In vivo model of myocardial ischemia-reperfusion(ischemia 40 minutes and reperfusion 2 hours) was established, hemodynamic parameters and electrocardiogram were recorded. The myocardial infarct size and death rate were estimated. Then the expression of m RN A of ANP, BNP, caspase-3, and Cx43 were screened on the heart after the IR.2. Rats were pretreated with S1P2/3 antagonist and heptanol, then conducted ischemia-reperfusion. The heart functional, ECG, as well as the hemodynamic parameters were recorded as prior. Immunohistochemical C x43 staining on cardiac tissues were analyzed.Results1. Compared with IR, the S1PR3 antagonist group and S1PR2/3 antagonist group showed significantly reduced heart rate(HR), and the maximal and minimal first derivatives of left ventricular press ure(+dp/dtmax), increased left ventricular end-diastolic pressure(LVEDP)(P<0.05), and increased the infarct size(55.68% vs 28.75%, 51.59% vs 28.75%) in I/R insulted rat hearts, while the S1PR3 agonist group the myocardial infarct size decreased(18.62% vs 28.75%). There was no ventricular fibrillation on sham group and control group. Compared with IR group, ventricular fibrillation in S1PR2/3 antagonist group was more frequency and longer- lasting(11%,28 s vs 25% 494s). Compared with control group, there was no prominent difference on expression of ANP, BNP, caspase-3, and Cx43, on the level of m RNA in heart.2. Compared with the IR group, the heptanol could reduce the infarction size(infarction area 18.78% vs 28.75%,P<0.05) and arrhythmia scores. Compared with S1PR2/3 antagonist pretreated group, the applying of heptanol had smaller infarct size(39.27% vs 51.59%,P<0.05), lower arrhythmia scores and mortality(P>0.05). Cx43 was located in intercalated discs of myocardium, and the amount of C x43 was normal in control group and sham operation group. IR induced C x43 remodeling that the expression of C x43 was decreased and distributed to the sides of the cardiomyocyte. The S1P2/3 antagonist group increased heterogeneity and lateralization of C x43 distr ibution. Pretreated with heptanol could stabilized the Cx43, decreased the remodeling.Conclusions1. S1PR2/3 had a beneficial effect on heart and reduced the mortality during myocardial ischemia-reperfusion in vivo. S1PR2/3 were involved in the Sudden cardiac death induced by IR injury.2. Cx43 mediated by S1PR2/3 is one of reasons that lead to SCD during IR.