Cardioprotective Effects Of Sevoflurane Postconditioning Inhypercholesterolemic Rats And Its Relationship To The Newly Identified Membranerepairing Protein MG53

Objective::Now, most animal researches about volatile anesthetic postconditioning used normal objects, but a lot of patients with myocardial ischemia were accompanied by other pathological conditions, such as hypercholesterolemia, etc.. Therefore, we must carry out preclinical animal experiments on hypercholesterolemia animal models. Although recent studies have suggested that MG53, a TRIM-containing family protein, plays an important role in cardioprotection, few studies address the role of MG53in sevoflurane postconditioning (SPO)-mediated protection against myocardial ischemia/reperfusion (I/R) injury. Here we also sought to explore the role and mechanism of MG53in SPO-mediated myocardial protection in a rat I/R model.Methods:On the Langendorff system, the isolated rat heart was subjected to40min global ischemia and120min reperfusion and, if necessary, received2.5%(v/v) sevoflurane postconditioning (10min) at the beginning of reperfusion. The left ventricular hemodynamic parameters, myocardial infarct size and the expression of myocardial MG53was were determined. Normocholesteolemic or hypercholesterolemic rat hearts in vivo were subjected to30min of ischemia and2h of reperfusion, with seovoflurane postconditioning, ischemic postconditioning (IPO), GSK inhibitor SB216763, or N-(2-mercaptopropionyl)-glycine (MPG), a reactive oxygen species (ROS) scavenger. The left ventricular hemodynamic, infarct size, apoptosis, MG53, PI3K-p85, p-Akt, p-ERK, p-STAT-3, p-GSK-3β were determined.Results:As for isolated hearts, The hemodynamic parameters were significantly improved and the myocardial infarct size was significantly reduced by SPO compared with those in the IR group. The expressions of MG53were markedly enhanced in SPO group compared with those in the I/R group (P<0.01). As for hearts in vivo, Infarct size expressed as a percentage of area at risk and myocardial apoptosis was larger in hypercholesterolemic rats than in normocholesterolemic ones, SB216763(but not sevoflurane) reduced myocardial infarct size and apoptosis in hypercholesterolemic subjects, while both agents reduced infarct size and myocardial apoptosis in normocholesterolemic ones compared with their respective control groups. Sevofluane and ischemic postconditioning-induced the improving left ventricular pump function and elevations of MG53, PI3K-p85, p-Akt, p-ERK1/2, P-GSK3β and in normocholesteolemic rats were blunted in hypercholesterolemic ones.Conclusions:In summary, Our findings confirm that MG53participates in SPO-mediated cardioprotection and we report that sevoflurane-induced cardioprotection against IR injury was abrogated in hypercholesterolemic rats. Hypercholesterolemia blocked the ability of sevoflurane to phosphorylate components of RISK pathway and consequently, the phosphorylation of the downstream target GSK-3β. These data indicts that direct inhibition of GSK3β before myocardial infarct may be a potential therapeutic approach to prevent IR injury in the presence of hypercholesterolemia.