5 - Intracellular signaling during myocardial ischemia

Summary

Introduction

There are several general points to be considered with respect to the perturbations in intracellular signaling that are induced by ischemia and any subsequent reperfusion, and these apply equally to the myocardium and to other tissues. First, what are the changes in the activities of signaling pathways wrought by prolonged periods of ischemia and are these related to any subsequent pathologies? Second, what are the mediators that lead to activation of these signaling pathways and what are the cellular sensors of these mediators? Third, what are the changes that allow short periods of ischemia to be protective against a subsequent period of ischemia that would normally inevitably lead to irreversible myocardial damage (the phenomenon known as ischemic conditioning)? Finally, what are the pharmacological options for intervention so that the damaging effects of ischemia and ischemia–reperfusion can be moderated or the protective effects of conditioning be stimulated? These questions are especially pertinent to the myocardium because the contractile cells (the cardiac myocytes) are terminally differentiated in the adult (i.e., they are incapable of undergoing a complete cycle of cell division), having withdrawn from the cell cycle during the perinatal period. This renders the heart particularly vulnerable to myocyte death such as that occurring during ischemic heart disease because the myocytes that are lost cannot be replaced, and the only palliative alternative is the regional expansion of the preexisting myocyte pool, i.e., cardiac remodeling.

Ischemia and ischemia–reperfusion are associated with gross disturbances in ionic balance and metabolic activity, and increases in the production of reactive oxygen species (ROS).