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.
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 hypercholesterolemicrat 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: Pu Duann; Haichang Li; Peihui Lin; Tao Tan; Zhen Wang; Ken Chen; Xinyu Zhou; Kristyn Gumpper; Hua Zhu; Thomas Ludwig; Peter J Mohler; Brad Rovin; William T Abraham; Chunyu Zeng; Jianjie Ma Journal: Sci Transl Med Date: 2015-03-18 Impact factor: 17.956
Authors: Hiroko Ishiwata-Endo; Jiro Kato; Akihiko Tonouchi; Youn Wook Chung; Junhui Sun; Linda A Stevens; Jianfeng Zhu; Angel M Aponte; Danielle A Springer; Hong San; Kazuyo Takeda; Zu-Xi Yu; Victoria Hoffmann; Elizabeth Murphy; Joel Moss Journal: JCI Insight Date: 2018-11-15
Authors: Hanley Ma; Jason Liu; Zehua Bian; Yuqi Cui; Xinyu Zhou; Xuefeng Zhou; Bo Zhang; T M Ayodele Adesanya; Frank Yi; Ki Ho Park; Tao Tan; Zhishui Chen; Hua Zhu Journal: PLoS One Date: 2015-05-07 Impact factor: 3.240