Signalling pathways and mechanisms of protection in pre- and postconditioning: historical perspective and lessons for the future

Abstract

Ischaemic pre- and postconditioning are potent cardioprotective interventions that spare ischaemic myocardium and decrease infarct size after periods of myocardial ischaemia/reperfusion. They are dependent on complex signalling pathways involving ligands released from ischaemic myocardium, G-protein-linked receptors, membrane growth factor receptors, phospholipids, signalling kinases, NO, PKC and PKG, mitochondrial ATP-sensitive potassium channels, reactive oxygen species, TNF-α and sphingosine-1-phosphate. The final effector is probably the mitochondrial permeability transition pore and the signalling produces protection by preventing pore formation. Many investigators have worked to produce a roadmap of this signalling with the hope that it would reveal where one could intervene to therapeutically protect patients with acute myocardial infarction whose hearts are being reperfused. However, attempts to date to show efficacy of such an intervention in large clinical trials have been unsuccessful. Reasons for this inability to translate successes in the experimental laboratory to the clinical arena are evaluated in this review. It is suggested that all patients with acute coronary syndromes currently presenting to the hospital and being treated with platelet P2Y12 receptor antagonists, the current standard of care, are indeed already benefiting from protection from the conditioning pathways outlined earlier. If that proves to be the case, then future attempts to further decrease infarction will have to rely on interventions which protect by a different mechanism.

Figure 1

Proposed signalling scheme for conditioning. Abbreviations: Brady, bradykinin; eNOS, endothelial NOS; K_ATP, ATP-dependent potassium channel; MEK, MAPK kinase; MMP, matrix metalloproteinase; p70S6K, p70S6 kinase; PDK1/2, 3′-phosphoinositide-dependent kinase-1/-2; PI_3,4,5P₃, phosphatidylinositol trisphosphate; PI_4,5P₂, phosphatidylinositol bisphosphate; Pro, pro-HB-EGF; Sphingo 1-P, sphingosine 1-phosphate; Src, sarcoma tyrosine kinase; TNF, TNF-α; Tyr, tyrosine. Modified from Tissier et al. (2007a).

Figure 2

Signalling during ischaemic pre- and postconditioning and effect of pH and transient reoxygenation on that signalling and mPTP formation. See Figure 1 for abbreviations. Modified from Cohen et al. (2007b; 2008).