AUTHOR=Bell James R. , Vila-Petroff Martin , Delbridge Lea M. D. 

TITLE=CaMKII-dependent responses to ischemia and reperfusion challenges in the heart

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 5 - 2014

YEAR=2014

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2014.00096

DOI=10.3389/fphar.2014.00096

ISSN=1663-9812

ABSTRACT=Ischemic heart disease is a leading cause of death, and there is considerable imperative to identify effective therapeutic interventions. Cardiomyocyte Ca2+ 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 Ca2+, Ca2+/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 Ca2+ 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.