Hyperlipidemia Impairs The Cardio Protective Effect Of Sevoflurane Postconditioning By Inhibiting RISK Signaling Pathway

Background:A lot of evidence suggests that volatile anesthetics postconditioning exert important cadioprotective effects and hypercholesterolemia increase cardiomyocyte apoptosis following ischemia and reperfusion. The aim of the current study was to determine whether hypercholesterolemia affects the sevoflurane postconditioning against myocardial ischemia-reperfusion (IR) injury and, if so, the underlying mechanism.Methods:Normocholesterolemic and hypercholesterolemic rats were randomly subjected to30-min ischemia/reperfusion, sevo-postC, with and without LY294002, a specific inhibitor of PI3K, and PD98059, a specific ERK inhibitor. The hemodynamic parameters left ventricular developed pressure, left ventricular end-diastolic pressure, and maximal rise/fall rate of left ventricular pressure were continuously monitored and myocardial infarct size was determined at the end of reperfusion. The protein expression of myocardial Akt, P-Akt, Erk1/2, P-Erk1/2, GSK3β, P-GSK3β, Bcl-2, Caspase-3were assessed.Results:Sevo-postC significantly reduced infarct size in the normocholesterolemic rats (34.4±7.6%, VS54.9±5.6%, P<0.01), a phenomenon completely reversed by LY294002and PD98059. Hypercholesterolemia blocked the protective effect of Sevo-postC, protein kinase B (Akt)/extracellular signal regulating kinase (Erkl/2)/GSK-3βwas significantly increased after ischemia-reperfusion and was further enhanced in response to ischemic Sevo-postC (P<0.05) but was not found in hypercholesterolemic rats. Meanwhile, hypercholesterolemic rats exhibited a more pronounced decrease in the expression of Bcl-2and a markedly increased activation of cleaved caspase-3within the ischemic myocardium compared to control rats.Conclusions:The effective reduction in infarct size in the normocholesterolemic rat heart by Sevo-postC was completely abrogated in hypercholesterolemic rats. The RISK pathway was involved in the mechanism of Sevo-postC. The ineffectiveness of Sevo-postC in hypercholesterolemic rats may be associated not only with the depressed Akt, Erkl/2and GSK-3βactivation but also with upregulated activation of caspase-3and downregulation of Bcl-2.