title: Hypercholesterolemic myocardium is vulnerable to ischemia-reperfusion injury and refractory to sevoflurane-induced protection.
abstract: Recent studies have demonstrated that volatile anesthetic postconditioning confers myocardial protection against ischemia-reperfusion (IR) injury through activation of the reperfusion injury salvage kinase (RISK) pathway. As RISK has been shown to be impaired in hypercholesterolemia. Therefore, we investigate whether anesthetic-induced cardiac protection was maintained in hypercholesterolemic rats. In the present study, normocholesteolemic or hypercholesterolemic rat hearts were subjected to 30 min of ischemia and 2 h of reperfusion. Animals received 2.4% sevoflurane for 5 min or 3 cycles of 10-s ischemia/10-s reperfusion. The hemodynamic parameters, including left ventricular developed pressure, left ventricular end-diastolic pressure and heart rate, were continuously monitored. The infarct size, apoptosis, p-Akt, p-ERK1/2, p-GSK3β were determined. We found that both sevoflurane and ischemic postconditioning significantly improved heart pump function, reduced infarct size and increased the phosphorylation of Akt, ERK1/2 and their downstream target of GSK3β in the healthy rats. In the hypercholesterolemic rats, neither sevoflurane nor ischemic postconditioning improved left ventricular hemodynamics, reduced infarct size and increased the phosphorylated Akt, ERK1/2 and GSK3β. In contrast, GSK inhibitor SB216763 conferred cardioprotection against IR injury in healthy and hypercholesterolemic hearts. In conclusions, hyperchoesterolemia abrogated sevoflurane-induced cardioprotection against IR injury by alteration of upstream signaling of GSK3β and acute GSK inhibition may provide a novel therapeutic strategy to protect hypercholesterolemic hearts against IR injury.
authors.affiliation: Department of Anesthesiology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejaing, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.forename: Lei-Lei
authors.initials: LL
authors.lastname: Ma
authors.forename: Chen
authors.initials: C
authors.lastname: Zhou
authors.forename: Fei-Jiang
authors.initials: FJ
authors.lastname: Zhang
authors.forename: Fei-Juan
authors.initials: FJ
authors.lastname: Kong
authors.forename: Wen-Na
authors.initials: WN
authors.lastname: Wang
authors.forename: Ling-Bo
authors.initials: LB
authors.lastname: Qian
authors.forename: Can-Can
authors.initials: CC
authors.lastname: Wang
authors.forename: Xian-Bao
authors.initials: XB
authors.lastname: Liu
authors.forename: Min
authors.initials: M
authors.lastname: Yan
authors.forename: Jian-An
authors.initials: JA
authors.lastname: Wang
mesh_terms: D018685:Anesthetics, Inhalation / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D003324:Coronary Artery Disease / Q000209:etiology / Q000473:pathology; D004032:Diet; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D006937:Hypercholesterolemia / Q000150:complications*; D057775:Ischemic Postconditioning; D008297:Male; D008738:Methyl Ethers / Q000008:administration & dosage / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D049288:Muscular Dystrophies, Limb-Girdle / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D000077149:Sevoflurane
chemical_list: D018685:Anesthetics, Inhalation; D002316:Cardiotonic Agents; D008738:Methyl Ethers; D000077149:Sevoflurane; D019869:Phosphatidylinositol 3-Kinases; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D038362:Glycogen Synthase Kinase 3