Postconditioning against ischaemia-reperfusion injury: ready for wide application in patients?

Abstract

Ischaemic postconditioning (IPOC) is an intervention in which brief, intermittent periods of reocclusion at the onset of reperfusion (i.e. stuttering reperfusion) protect myocardium from lethal reperfusion injury. The mechanism underlying the cardioprotective effects of IPOC is incompletely understood. However, it is perceived that IPOC begins with specific cell-surface receptors responsible for activating a number of signalling pathways, many of which appear to converge at the mitochondrial level. IPOC has been demonstrated both in animal models and in patients with acute myocardial infarction (AMI) in small proof-of-concept trials. This intervention offers the possibility of further limiting infarct size in patients undergoing primary percutaneous coronary intervention (PCI). Here, we provide a brief overview of the concept of IPOC and the mechanisms underlying this phenomenon. (Neth Heart J 2010;18:389-93.).

Keywords: Myocardial; Myocardial Ischemia; Myocardial Reperfusion Injury; Signal Transduction.

Figure 1

A) Overview of the potential mechanisms linking ischaemic postconditioning (IPOC) to the mitochondrial permeability transition pore (mPTP). These can be divided into direct and indirect effects of IPOC. The direct effects start with a number of autocoids including adenosine, bradykinin and opioids accumulating in the postconditioned myocardium and acting on their cell-surface receptors. The activation of cell-surface receptors recruits signalling cascades including the Akt and extracellular signal-regulated kinase (ERK1/2) components of the reperfusion injury salvage kinase (RISK) pathway. Activated Akt phosphorylates multiple substrates, including endothelial nitric oxide synthase (eNOS) and glycogen synthase kinase 3β (GSK-3β). Phosphorylation of eNOS activates the protein kinase G (PKG) through elevated guanosine 3’,5’-cyclic monophosphate (cGMP), thereby recruiting protein kinase C (PKC) and possibly inhibiting the mPTP. The ERK1/2 pathway may be crucial in inactivation of GSK-3β (through phosphorylation) and thereby preventing mPTP opening, an effect that may also be activated by Akt. The indirect effects of IPOC include calcium regulation, attenuation of oxidative stress and delaying pH correction at reperfusion. Ultimately, mPTP opening during early reperfusion is inhibited by these various effects, leading to ATP preservation and cell survival. B) Abrupt restoration of the blood flow to the ischaemic myocardium can cause irreversible damage through effects such as calcium overload, oxidative stress and a rapid restoration of neutral pH, among others, which are factors known to induce mPTP opening at the time of reperfusion. Ultimately, mPTP opening during early reperfusion is induced by these various effects, resulting in ATP depletion and cell death. GC=guanylyl cyclase, MAPK = mitogen-activated protein kinase, NO=nitric oxide, PI3K=phosphoinositide 3 kinase.

Figure 1

A) Overview of the potential mechanisms linking ischaemic postconditioning (IPOC) to the mitochondrial permeability transition pore (mPTP). These can be divided into direct and indirect effects of IPOC. The direct effects start with a number of autocoids including adenosine, bradykinin and opioids accumulating in the postconditioned myocardium and acting on their cell-surface receptors. The activation of cell-surface receptors recruits signalling cascades including the Akt and extracellular signal-regulated kinase (ERK1/2) components of the reperfusion injury salvage kinase (RISK) pathway. Activated Akt phosphorylates multiple substrates, including endothelial nitric oxide synthase (eNOS) and glycogen synthase kinase 3β (GSK-3β). Phosphorylation of eNOS activates the protein kinase G (PKG) through elevated guanosine 3’,5’-cyclic monophosphate (cGMP), thereby recruiting protein kinase C (PKC) and possibly inhibiting the mPTP. The ERK1/2 pathway may be crucial in inactivation of GSK-3β (through phosphorylation) and thereby preventing mPTP opening, an effect that may also be activated by Akt. The indirect effects of IPOC include calcium regulation, attenuation of oxidative stress and delaying pH correction at reperfusion. Ultimately, mPTP opening during early reperfusion is inhibited by these various effects, leading to ATP preservation and cell survival. B) Abrupt restoration of the blood flow to the ischaemic myocardium can cause irreversible damage through effects such as calcium overload, oxidative stress and a rapid restoration of neutral pH, among others, which are factors known to induce mPTP opening at the time of reperfusion. Ultimately, mPTP opening during early reperfusion is induced by these various effects, resulting in ATP depletion and cell death. GC=guanylyl cyclase, MAPK = mitogen-activated protein kinase, NO=nitric oxide, PI3K=phosphoinositide 3 kinase.