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Hypercholesterolemia blocked sevoflurane-induced cardioprotection against ischemia-reperfusion injury by alteration of the MG53/RISK/GSK3β signaling
- Source :
- International journal of cardiology. 168(4)
- Publication Year :
- 2012
-
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 30min of ischemia and 2h of reperfusion. Animals received 2.4% sevoflurane during three 5min periods with and without PI3K antagonist wortmannin (10μg/kg, Wort) or the ERK inhibitor PD 98059 (1mg/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.
- Subjects :
- Male
Methyl Ethers
Cardiotonic Agents
Hypercholesterolemia
Ischemia
Myocardial Reperfusion Injury
Pharmacology
Sevoflurane
Wortmannin
Rats, Sprague-Dawley
chemistry.chemical_compound
Glycogen Synthase Kinase 3
medicine
Animals
Protein kinase B
PI3K/AKT/mTOR pathway
Cardioprotection
Glycogen Synthase Kinase 3 beta
business.industry
Antagonist
Membrane Proteins
medicine.disease
Rats
chemistry
Anesthesia
Cardiology and Cardiovascular Medicine
business
Carrier Proteins
Reperfusion injury
medicine.drug
Signal Transduction
Subjects
Details
- ISSN :
- 18741754
- Volume :
- 168
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- International journal of cardiology
- Accession number :
- edsair.doi.dedup.....a235963e2c432f2c01e7fd751854a795