Signaling pathways in ischemic preconditioning James M. Downey Æ Amanda M. Davis Æ Michael V. Cohen Published online: 22 May 2007 Ó Springer Science+Business Media, LLC 2007 Abstract Ischemic preconditioning renders the heart resistant to infarction from ischemia/reperfusion. Over the past two decades a great deal has been learned about pre- conditioning’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-3b. 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. Keywords Akt Á G i protein-coupled receptors Á Mitochondrial permeability transition pore Á Nitric oxide Á PI3-kinase Á PKC Á Preconditioning Á Reactive oxygen species Introduction According to the World Health Organization, acute myocardial infarction (MI) is the leading cause of death throughout the world in both men and women. The myocardial injury incurred during coronary thrombosis is caused by decreased flow which results in lack of nutri- tion to the tissue. Prolonged lack of nutrition leads to tissue death, i.e., infarction. The ultimate goal when treating patients with acute MI is to return blood flow to the occluded area as soon as possible to salvage the most ischemic tissue. Infarcted tissue does not regenerate and thus loss of contractile mass results in a permanently compromised ventricle. Since irreversible damage begins to occur within approximately 20 min of occlusion and is complete within 6 h, reperfusion should be accomplished as soon as possible. It should be noted that there is concern that reperfusion itself may cause tissue injury. Thus, while reperfusion is necessary to salvage the myocardium, it may also kill some of the tissue in the process. Finding a way to render the heart resistant to ischemia and/or reduce reperfusion injury would undoubtedly improve the outcome following acute MI. While much of current treatment is devoted to treating arrhythmias and remodeling associated with infarction, surprisingly little is being done to promote myocardial salvage during the acute phase in these patients other than simply reducing the delay before reperfusion. J. M. Downey Á A. M. Davis Á M. V. Cohen Department of Physiology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA M. V. Cohen (&) Department of Medicine, MSB 3050, College of Medicine, University of South Alabama, Mobile, AL 36688, USA e-mail: mcohen@usouthal.edu 123 Heart Fail Rev (2007) 12:181–188 DOI 10.1007/s10741-007-9025-2