Received for publication December 27, 2005.
Revised March 18, 2006.
Accepted for publication March 21, 2006.

Volatile Anesthetic Preconditioning Attenuates Myocardial Apoptosis in Rabbits after Regional Ischemia and Reperfusion via Akt Signaling and Modulation of Bcl-2 Family Proteins

Abstract

We tested whether isoflurane preconditioning inhibits cardiomyocyte apoptosis and evaluated the role of the phosphatidylinositol-3-kinase (PI3K)/Akt pathway in anesthetic preconditioning and determined whether (PI3K)/Akt signaling modulates the expression of pro- and anti-apoptotic proteins in anesthetic preconditioning. Six-months old New-Zealand rabbits subjected to 40 minutes of myocardial ischemia followed by 180 minutes of reperfusion, were assigned to the following groups: ischemia-reperfusion (I/R), isoflurane preconditioning and isoflurane plus PI3K inhibitors: wortmannin and LY294002 (0.6 mg/kg, 0.3 mg/kg intravenously, respectively). Sham-operated, wortmannin + I/R, wortmannin + sham, LY294002 + I/R and LY294002 + sham groups were also included. Infarct size was assessed by triphenyltetrazolium chloride staining. Apoptosis was evaluated by TUNEL and activated caspase-3 assays. Akt phosphorylation, Bax, Bcl-2, Bad and phospho-Bad expression was assessed by immunoblotting. Isoflurane preconditioning reduced infarct size compared to the I/R group: 22±4% vs. 41±5% (p<0.05). The percentage of apoptotic cells decreased in the isoflurane group (3.8±1.2%) compared to I/R group (12.4±1.6%; p<0.05). These results were also confirmed by the activated caspase-3 assay. Wortmannin and LY294002 inhibited the effects of isoflurane: myocardial infarction increased to 44±3% and 45±2% and the percentage of apoptotic cells was 11.9±2.1% and 11.7±3.3% respectively. Akt phosphorylation, Bcl-2 and phospho-Bad expression increased after isoflurane preconditioning, while Bax expression decreased. These effects were inhibited by wortmannin and LY294002. The data indicate that isoflurane preconditioning reduces infarct size and myocardial apoptosis after I/R. Activation of PI3K and modulation of the expression of pro- and anti-apoptotic proteins may play a role in isoflurane-induced myocardial protection.

Key words: Anesthetics, Apoptosis, Ischemia, PI3K, Preconditioning, Reperfusion

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