Hypercholesterolemia blocked sevoflurane-induced cardioprotection against ischemia–reperfusion injury by alteration of the MG53/RISK/GSK3β signaling

LL Ma, FJ Zhang, LB Qian, FJ Kong, JF Sun… - International journal of …, 2013 - Elsevier
LL Ma, FJ Zhang, LB Qian, FJ Kong, JF Sun, C Zhou, YN Peng, HJ Xu, WN Wang, CY Wen…
International journal of cardiology, 2013Elsevier
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 …
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.
Elsevier