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Ca 2+ /calmodulin dependent kinase II : A critical mediator in determining reperfusion outcomes in the heart?
Author(s) -
Bell James R,
Erickson Jeffrey R,
Delbridge Lea MD
Publication year - 2014
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/1440-1681.12301
Subject(s) - ischemia , inotrope , endoplasmic reticulum , calmodulin , mediator , reperfusion injury , microbiology and biotechnology , mitochondrion , myocardial stunning , medicine , chemistry , calcium , cardiology , biology
Summary 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 (Ca MKII ) 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, Ca MKII targets numerous Ca 2+ channels/transporters involved in Ca 2+ handling and contractile function regulation. Ca MKII is activated early in reperfusion, where it exacerbates Ca 2+ leak from the sarcoplasmic reticulum and promotes the onset of ventricular arrhythmias. Inhibiting Ca MKII 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, Ca MKII 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 Ca MKII as a part of a surgical reperfusion strategy, though further mechanistic understanding of the relationship between Ca MKII activation status and the extent of ischaemia/reperfusion injury are required to fully establish an optimal pharmacological approach.