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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anesthetics, Inhalation / administration & dosage
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Anesthetics, Inhalation / pharmacology*
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Animals
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Apoptosis / drug effects
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Cardiotonic Agents / administration & dosage
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Cardiotonic Agents / pharmacology*
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Coronary Artery Disease / etiology
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Coronary Artery Disease / pathology
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Diet
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Glycogen Synthase Kinase 3 / antagonists & inhibitors
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Heart Ventricles / drug effects
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Heart Ventricles / physiopathology
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Hemodynamics / drug effects
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Hypercholesterolemia / complications*
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Ischemic Postconditioning
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Male
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Methyl Ethers / administration & dosage
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Methyl Ethers / pharmacology*
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / metabolism
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Muscular Dystrophies, Limb-Girdle / metabolism
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Myocardial Reperfusion Injury / drug therapy
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Myocardial Reperfusion Injury / etiology*
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Myocardial Reperfusion Injury / pathology
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Myocardium / metabolism*
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Phosphatidylinositol 3-Kinases / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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Rats
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Sevoflurane
Substances
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Anesthetics, Inhalation
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Cardiotonic Agents
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Methyl Ethers
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Sevoflurane
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Phosphatidylinositol 3-Kinases
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, rat
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Glycogen Synthase Kinase 3
Grants and funding
This work was supported by the Natural Science Foundation of China (numbers 81170118 and 81201496), the Natural Science Foundation of Zhejiang Province (number R2090259), Medicine Administration Bureau of Zhejiang Province (number 2011ZZ009), and the Foundation from Science and Technology Department of Zhejiang Province (numbers 2009C13G2010218 and 2012C33088). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.