Ca²⁺/calmodulin dependent kinase II: A critical mediator in determining reperfusion outcomes in the heart?

Abstract

Ischaemic heart disease is a major cause of death and disability in the Western world, and a substantial health burden. Cardiomyocyte Ca(2+) overload is known to significantly contribute to contractile dysfunction and myocyte death in ischaemia and reperfusion, and significant advancements have been made in identifying the downstream mediators and cellular origins of this Ca(2+) mismanagement. Ca(2+) /calmodulin-dependent kinase II (CaMKII) is recognized as an important mediator linking pathological changes in subcellular environments to modifications in cardiomyocyte Ca(2+) handling. Activated in response to fluctuations in cellular Ca(2+) and to various post-translational modifications, CaMKII targets numerous Ca(2+) channels/transporters involved in Ca(2+) handling and contractile function regulation. CaMKII is activated early in reperfusion, where it exacerbates Ca(2+) leak from the sarcoplasmic reticulum and promotes the onset of ventricular arrhythmias. Inhibiting CaMKII can increase functional recovery in reperfusion and reduce apoptotic/necrotic death, at least partly through indirect and direct influences on mitochondrial Ca(2+) levels and function. Yet, CaMKII can also have beneficial actions in ischaemia and reperfusion, in part by providing inotropic support for the stunned myocardium and contributing as an intermediate to cardioprotective preconditioning signalling cascades. There is considerable potential in targeting CaMKII as a part of a surgical reperfusion strategy, though further mechanistic understanding of the relationship between CaMKII activation status and the extent of ischaemia/reperfusion injury are required to fully establish an optimal pharmacological approach.

Excitotoxic Insult Results in a Long-Lasting Activation of CaMKIIα and Mitochondrial Damage in Living Hippocampal Neurons

“…In ischemic heart, CaMKII autonomous activation has been suggested to play a critical role in promoting cell damage, though the mechanisms are not completely understood [ 66 , 67 , 68 ]. Recent studies also implicated the autonomous state of CaMKII in neuronal damage produced by ischemia/excitotoxicity [ 2 , 4 ], but that mechanisms are also not clear.…”

“…Therefore, it is plausible that the persistence of CaMKII activation after excitotoxic insult is controlled by Ca 2+ deregulation, which at least in part depends on mitochondrial damage. In addition, over-activated CaMKII itself has a potential to promote the toxic deregulation of Ca 2+ homeostasis [ 66 , 67 , 68 , 76 ].…”

Yap promotes hepatocellular carcinoma metastasis and mobilization via governing cofilin/F-actin/lamellipodium axis by regulation of JNK/Bnip3/SERCA/CaMKII pathways

“…Apart from mitochondria, cellular migration also needs moderate intercellular calcium ([Ca 2+ ]i) concentration [24] . The excessive [Ca 2+ ]i elevation would impair the cellular migration via activation of Ca/calmodulin-dependent protein kinases II (CaMKII) [25] . The CaMKII has the ability to phosphorylate cofilin [26] .…”

Myocardial death and dysfunction after ischemia-reperfusion injury require CaMKIIδ oxidation

“…CaMKII is initially activated by binding to calcified calmodulin, but oxidation of regulatory domain methionines, at positions 281 and 282, contributes to persistent calmodulin-autonomous CaMKII activity by preventing autoinhibition 10 . Excessive CaMKII activity is implicated in myocardial death, including in I/R injury 11,12 , suggesting that oxidized CaMKII (ox-CaMKII) could be an important, but previously unexplored, pathological signal in I/R injury. We performed I/R surgery on a knock-in mouse model of ROS resistant CaMKIIδ, the predominant myocardial isoform, where methionines 281/282 were replaced with valines (MMVV) 13,14 , and discovered that MMVV hearts were protected from myocardial death and dysfunction, consistent with the hypothesis that ox-CaMKII is an important step for ROS transduction in I/R injury.…”