Signaling pathways in ischemic preconditioning

Abstract

Ischemic preconditioning renders the heart resistant to infarction from ischemia/reperfusion. Over the past two decades a great deal has been learned about preconditioning's mechanism. Adenosine, bradykinin, and opioids act in parallel to trigger the preconditioned state and do so by activating PKC. While adenosine couples directly to PKC through the phospholipases, bradykinin and opioids do so through a complex pathway that includes in order: phosphatidylinositol 3-kinase (PI3-kinase), Akt, nitric oxide synthase, guanylyl cyclase, PKG, opening of mitochondrial K(ATP) channels, and activation of PKC by redox signaling. There are even differences between the opioid and bradykinin coupling as the former activates PI3-kinase through transactivation of the epidermal growth factor receptor while the latter has an unknown coupling mechanism. Protection stems from inhibition of formation of mitochondrial permeability transition pores early in reperfusion through activation of the survival kinases, Akt and ERK. These kinases are activated as a result of PKC somehow promoting signaling from adenosine A(2) receptors early in reperfusion. The survival kinases are thought to inhibit pore formation by phosphorylating GSK-3beta. The reperfused heart requires the support of the protective signals for only about an hour after which the ischemic injury is repaired and the signals are no longer needed.

Ischemic preconditioning of the liver: A few perspectives from the bench to bedside translation

“…Over the next 2 decades extensive research further elucidated the temporal phases of IPC, the initiating triggers, and the other mechanistic aspects of this endogenous protective mechanism in diverse organs and species including humans; studies which are well summarized in recent reviews of this topic. [10][11][12][13][14][15] In laboratory animals and humans, IPC of the liver may be induced either by a single short period of ischemia or multiple short cycles of ischemia (or intermittent hilar clamping). 16 In a rat liver transplant model, Yin et al 2 investigated single IPC periods ranging between 5 and 20 minutes and showed that 10 minutes induced the best protection.…”

Myocardial ischemia-reperfusion and cardioprotection: a study with microdialysis in a porcine model

“…Intensive research has been performed on the signalling pathways. Several triggers, mediators, and effectors have been identified (Yellon 2003, Zaugg 2003, Downey 2007. The entire mechanism, or probably several pathways, has not been fully elucidated.…”

“…The entire mechanism, or probably several pathways, has not been fully elucidated. One important key seems to be the ATP-sensitive potassium channels, KATP channels (Gross 2003, Yellon 2003, Zaugg 2003, Downey 2007. Experiments with different activators and inhibitors of these channels have demonstrated their role in inducing myocardial preconditioning when activated (Gross 2003, Yellon 2003.…”

“…The channels are ATP-sensitive and are inhibited by physiological concentrations of ATP (Yellon 2003). Some important pathways, by which the opening of KATP channels induces protection to the myocardium, are probably interactions with protein kinase C, reactive oxygen species, and inhibition of the mitochondrial permeability transition pore (Yellon 2003, Zaugg 2003, Downey 2007, Hausenloy 2009). The last is supposed to be an end-effector of cell death (Monassier 2008).…”

Hind limb ischemic preconditioning induces an anti-inflammatory response by remote organs in rats

“…These include activation of G protein-coupled receptors, protein kinase C, mitogen-activated protein kinases, ATPsensitive K + channels, heat shock protein, adenosine, metal ions, oxygen and nitrogen reactive species, oxidized and biological active lipids, cytokines, catecholamines, and nitric oxide (NO) synthase (7,8).…”