Heart Failure Reviews

, Volume 12, Issue 3–4, pp 181–188 | Cite as

Signaling pathways in ischemic preconditioning

  • James M. Downey
  • Amanda M. Davis
  • Michael V. Cohen


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 KATP 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 A2 receptors early in reperfusion. The survival kinases are thought to inhibit pore formation by phosphorylating GSK-3β. 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.


Akt Gi protein-coupled receptors Mitochondrial permeability transition pore Nitric oxide PI3-kinase PKC Preconditioning Reactive oxygen species 


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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • James M. Downey
    • 1
  • Amanda M. Davis
    • 1
  • Michael V. Cohen
    • 1
    • 2
  1. 1.Department of Physiology, College of MedicineUniversity of South AlabamaMobileUSA
  2. 2.Department of Medicine, MSB 3050, College of MedicineUniversity of South AlabamaMobileUSA

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