Furthermore, we have demonstrated for the first time that this effect of RPO was significantly attenuated when these hearts were perfused with the PI3 Kinase inhibitor, wortmannin. Therefore, we can conclude that the RPO induced protection of the heart during ischemiareperfusion induced injury is, at Ganetespib least in part, mediated by the PI3 kinase pathway. In response to ischemiareperfusion induced injury, cells activate various signal transduction pathways which either may be harmful or allow adaptation to this stressful environment. There is an increasing body of evidence showing that PKBAkt may represent a nodal point to coordinate growth factor signaling in the early phase of ischemiareperfusion induced injury in the heart.

However, no knowledge exists about the possible involve ment of Inhibitors,Modulators,Libraries the PI3 KAkt pathway in RPO induced protec tion during ischemiareperfusion injury in the heart. Therefore, another aim of this study was to determine whether PI3 Kinase inhibition induced changes in protein phosphorylation and apoptosis in hearts subjected to ischemiareperfusion injury of animals which received dietary RPO supplementation. Upon growth factor activation of receptor tyrosine kinases, PI3 K is recruited to the receptor in the plasma membrane and phosphorylates phosphatidylinositol 4,5 bisphosphate on the 3 OH group, generating phos 4 phatidylinositol 3,4,5 trisphosphate. PI3 kinase is considered one of the intracellular signals responsible for the transmission of anti apoptotic signals for controlling cell survival.

Over expression of PI3 kinase in cells has been shown to cause a significant increase in survival of cells exposed to ionizing radiation. Kennedy and co workers also reported that inhibition of PI3 K causes an Although PKB promotes Inhibitors,Modulators,Libraries cell survival, the mechanisms involved have only recently begun to emerge. One means by which PKB may promote cell survival is by directly phosphorylating transcription Inhibitors,Modulators,Libraries factors that control the expression of pro and anti apoptotic genes. PKB appears to both negatively Inhibitors,Modulators,Libraries regulate factors that promote the expression of death genes and positively regulate factors that induce survival genes. An example is the fam ily of forkhead transcription factors. All the mem bers of the FKHR family contain a PKB phosphorylation sequence which can be effectively phosphorylated by PKB in vitro. Phosphorylation of FKHR by PKB alters its subcellular location.

FKHR phosphorylation was signifi cantly inhibited when RPO Wn was compared to the RPO group. This leads to forkhead proteins residing Inhibitors,Modulators,Libraries pre dominantly in the nucleus where they are able to promote administrationreceived RPO supplementation ischaemiareper The cleavage of PARP in hearts subjected to ischae miareperfusion that received RPO supplementation and Wortmannin administration. increase in apoptosis and a decrease in cell survival. PI3 kinases are composed of a catalytic subunit and U0126 ERK a regulatory subunit.