Ischemic heart disease is a leading cause of death, and there is considerable imperative to identify effective therapeutic interventions. Cardiomyocyte Ca(2+) overload is a major cause of
ischemia and
reperfusion injury, initiating a cascade of events culminating in cardiomyocyte death, myocardial dysfunction, and occurrence of lethal arrhythmias. Responsive to fluctuations in intracellular Ca(2+),
Ca(2+)/calmodulin-dependent protein kinase II (
CaMKII) has emerged as an enticing therapeutic target in the management of ischemic
heart injury.
CaMKII is activated early in
ischemia and to a greater extent in the first few minutes of reperfusion, at a time when reperfusion arrhythmias are particularly prominent.
CaMKII phosphorylates and upregulates many of the key
proteins involved in intracellular Na(+) and Ca(2+) loading in
ischemia and reperfusion. Experimentally, selective inhibition of
CaMKII activity reduces cardiomyocyte death and arrhythmic incidence post-
ischemia. New evidence is emerging that
CaMKII actions in
ischemia and reperfusion involve specific splice variant targeted actions, selective and localized post-translational modifications, and organelle-directed substrate interactions. A more complete mechanistic understanding of
CaMKII mode of action in
ischemia and reperfusion is required to optimize intervention opportunities. This review summarizes the current experimentally derived understanding of
CaMKII participation in mediating the pathophysiology of the heart in
ischemia and in reperfusion, and highlights priority future research directions.