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

Abstract

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.

Keywords: Ca2+ handling; CaMKII; cardiomyocyte death; contractile function; ischemia; reperfusion.

FIGURE 1

Overview of CaMKII activation and substrate interaction in reperfusion. Post-ischemic restoration of coronary flow re-establishes the trans-sarcolemmal proton gradient and stimulates Na⁺/H⁺ exchange. This promotes reverse-mode Na⁺/Ca²⁺ exchange and leads to intracellular Ca²⁺ overload. Ca²⁺-activated CaMKII upregulates many Ca²⁺-related channels/transporters, further increasing cytosolic/mitochondrial Ca²⁺ levels, and triggers the opening of the mitochondrial permeability transition pore. The increase in Ca²⁺ and reactive oxygen species generation creates a positive feedback on CaMKII and exacerbates ischemia/reperfusion injury. NCX, Na⁺/Ca²⁺ exchanger; NHE, Na⁺/H⁺ exchanger; NKA, Na⁺/K⁺-ATPase; LTCC, L-type Ca²⁺ channel; SR, sarcoplasmic reticulum; SERCA2a, sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase; PLB, phospholamban; ROS, reactive oxygen species; mPTP, mitochondrial permeability transition pore.

FIGURE 2

CaMKII inhibition reduces ischemic contracture and reperfusion arrhythmias in male ex vivo hearts. Hearts subjected to ischemia/reperfusion were treated with a CaMKII inhibitor (KN93). (A) The amplitude of ischemic contracture was significantly lower in the presence of KN93, indicating CaMKII contributes to cardiomyocyte Ca²⁺ loading in ischemia. (B) Analysis of ventricular pressure traces showed a substantial reduction in the total duration of ventricular tachycardia and/or fibrillation in the first ten minutes of reperfusion in KN93-treated hearts. Data are expressed as mean ± SEM, *p <0.05 vs. control. Reproduced with permission (Elsevier, (Bell et al., 2012)).

FIGURE 3

Cell death in ischemia/reperfusion was suppressed by CaMKII inhibition. (A) Assessment of TTC stained heart cross-sections showed KN93 significantly reduced infarct size in ischemia/reperfusion. (B) Lower caspase 3 activation and less TUNEL positive cells in these hearts showed KN93 also reduced apoptosis in reperfusion. Data are expressed as mean ± SEM, *p <0.05 vs. control; ^#p <0.05 vs. I/R. Reproduced with permission (Oxford Journals, (Vila-Petroff et al., 2007)).