Role of phosphatidylinositol 3-kinase in the development of hepatocyte preconditioning.

摘要: Background & Aims:Ischemic preconditioning has been proved effective in reducing ischemia/reperfusion injury during liver surgery. However, the mechanisms involved are still poorly understood. Here, we have investigated role of phosphatidylinositol 3-kinase (PI3K) signal pathway leading to hepatic preconditioning. Methods:PI3K activation was evaluated isolated rat hepatocytes preconditioned by 10-minute hypoxia followed reoxygenation. Results:Hypoxic stimulated phosphatidylinositol-3,4,5-triphosphate production and phosphorylation PKB/Akt, a downstream target PI3K. Conversely, PI3K inhibition wortmannin or LY294002 abolished hepatocyte tolerance against hypoxic damage induced required stimulation adenosine A2A receptors mimicked agonist CGS21680. In cells treated with CGS21680, prevented either inhibiting adenylate cyclase PKA with, respectively, 2,5-dideoxyadenosine H89 blocking Gαi-protein Src tyrosine kinase pertussis toxin PP2. also receptors. direct forskolin failed stimulate This suggested that PKA-phosphorylated may activate coupling it through Src. We observed that, impairing PI3K-mediated phospholypase Cγ (PLCγ), blocked transduction signals via protein C (PKC) δ/ϵ isozymes. Conclusions:PI3K is activated following combined receptors, PKA, Gαi protein, By regulating PKC-ϵ/δ-dependent signals, can play key development hypoxia/reperfusion.