title: Hypercholesterolemia blocked sevoflurane-induced cardioprotection against ischemia-reperfusion injury by alteration of the MG53/RISK/GSK3β signaling.
abstract: BACKGROUND
  Recent studies have demonstrated that volatile anesthetic preconditioning 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, we investigate whether anesthetic-induced cardiac protection was maintained in hypercholesterolemic rats.
  
  
  METHODS
  Normocholesteolemic or hypercholesterolemic rat hearts were subjected to 30 min of ischemia and 2 h of reperfusion. Animals received 2.4% sevoflurane during three 5 min periods with and without PI3K antagonist wortmannin (10 μg/kg, Wort) or the ERK inhibitor PD 98059 (1 mg/kg, PD). The infarct size, apoptosis, p-Akt, p-ERK1/2, p-GSK3β were determined.
  
  
  RESULTS
  Two hundred and six rats were analyzed in the study. In the healthy rats, sevoflurane significantly reduced infarct size by 42%, a phenomenon completely reversed by wortmannin and PD98059 and increased the phosphorylation of Akt, ERK1/2 and their downstream target of GSK3β. In the hypercholesterolemic rats, sevoflurane failed to reduce infarct size and increase the phosphorylated Akt, ERK1/2 and GSK3β. In contrast, GSK inhibitor SB216763 conferred cardioprotection against IR injury in healthy and hypercholesterolemic hearts.
  
  
  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 310009, China. Electronic address: mllsdjn@163.com.
authors.forename: Lei-Lei
authors.initials: LL
authors.lastname: Ma
authors.forename: Feng-Jiang
authors.initials: FJ
authors.lastname: Zhang
authors.forename: Ling-Bo
authors.initials: LB
authors.lastname: Qian
authors.forename: Fei-Juan
authors.initials: FJ
authors.lastname: Kong
authors.forename: Jun-Feng
authors.initials: JF
authors.lastname: Sun
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhou
authors.forename: Yu-Nan
authors.initials: YN
authors.lastname: Peng
authors.forename: Hong-Jiao
authors.initials: HJ
authors.lastname: Xu
authors.forename: Wen-Na
authors.initials: WN
authors.lastname: Wang
authors.forename: Chuan-Yun
authors.initials: CY
authors.lastname: Wen
authors.forename: Man-Hua
authors.initials: MH
authors.lastname: Zhu
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Yu
authors.forename: Xian-Bao
authors.initials: XB
authors.lastname: Liu
authors.forename: Jian-An
authors.initials: JA
authors.lastname: Wang
authors.forename: Min
authors.initials: M
authors.lastname: Yan
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D002352:Carrier Proteins / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006937:Hypercholesterolemia / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins; D008738:Methyl Ethers / Q000494:pharmacology / Q000627:therapeutic use*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077149:Sevoflurane; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D002316:Cardiotonic Agents; D002352:Carrier Proteins; C538824:MG53 protein, mouse; D008565:Membrane Proteins; D008738:Methyl Ethers; D000077149:Sevoflurane; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3
keywords: Cardioprotection; GSK3β; Hypercholesterolemia; Preconditioning; Sevoflurane