Myocardial ischemia and ischemia/reperfusion activate several protein kinase pathways. Protein kinase activation potentially regulates the onset of myocardial cell injury and the reduction of this injury by ischemic and pharmacologic preconditioning. The primary protein kinase pathways that are potentially activated by myocardial ischemia/reperfusion include: the MAP kinases, ERK 1/2, JNK 1/2, p38 MAPKalpha/beta; the cell survival kinase, Akt; and the sodium-hydrogen exchanger (NHE) kinase, p90RSK. The literature does not support a role for ischemia/reperfusion in the activation of the tyrosine kinases, Src and Lck, or the translocation and activation of PKC. This review will detail the role of these protein kinases in the onset of myocardial cell death by necrosis and apoptosis and the reduction of this injury by preconditioning.

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The cardiomyocyte cytoskeleton is composed of a highly organised complex array of specific proteins, arranged to transmit mechanical forces within the cell, to adjacent cells and the extracellular matrix, as well as to maintain internal organisation of cellular organelles. Although most of the published reports on cytoskeletal proteins refer to non-myocyte and smooth muscle cells, there seem significant homologies with cardiac structures. The specific interactions of some proteins in certain cytoskeletal structures are established and may be analogous to interactions in cardiac myocytes, but the roles of many proteins are uncertain, and the list of proteins that compose the cytoskeleton is likely to be incomplete. Some proteins may serve a dual role, contributing to signal transduction as well as to organisation and mechanical stability of the cell. Phosphorylation of cytoskeletal proteins, and elaborate cellular systems to control protein phosphorylation levels, suggest phosphorylation as a potential mechanism of controlling cytoskeletal assembly and remodelling. Disturbances of the cytoskeleton during ischaemia may produce alterations in cell structural integrity that could account for cell injury and death. Although mechanisms both of cytoskeletal assembly in normal cells and of cytoskeletal injury in ischaemic cells are currently poorly understood, research into the interactions of cytoskeletal proteins during ischaemia includes new approaches that may increase our understanding of the pathophysiology of the cardiac myocyte.

Glucose-free preincubation protects ischaemic isolated myocytes from subsequent ischaemia. The degree of protection is great enough to account for protection seen in intact hearts, following preconditioning protocols. Protection is blocked by SPT and a highly specific protein kinase C inhibitor, calphostin C. Protection from ischaemic injury that seems to mimic ischaemic preconditioning can be induced in isolated cardiomyocytes, and appears dependent on adenosine receptors and activation of protein kinase C.

Preconditioning can be induced in isolated myocytes by a 5 min preincubation/30 min postincubation protocol, and a similar protection induced by adenosine agonists with A3, but not A1 selectivity. Preconditioning is blocked by non-selective or selective A1/A3 adenosine antagonists and a specific protein kinase C inhibitor, but not by A1 antagonists with little affinity for A3 receptors. The results suggest that preconditioning in isolated rabbit myocytes requires participation of adenosine receptors with agonist/antagonist binding characteristics of the A3 subtype, and is likely to be mediated by activation of protein kinase C.