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Ca(2+) /calmodulin dependent kinase II: a critical mediator in determining reperfusion outcomes in the heart?
James R Bell1, Jeffrey R Erickson, Lea Md Delbridge
1Department of Physiology, University of Melbourne, Melbourne, Vic., Australia.
Insights
Calcium/calmodulin-dependent kinase II (CaMKII) plays a dual role in heart attacks, worsening damage during reperfusion but also offering protection. Inhibiting CaMKII may improve recovery after heart surgery.
Area of Science:
- Cardiology
- Molecular Biology
- Biochemistry
Background:
- Ischaemic heart disease presents a significant global health challenge, leading to widespread death and disability.
- Cardiomyocyte calcium overload is a key factor in contractile dysfunction and cell death during ischaemia and reperfusion.
- Calcium/calmodulin-dependent kinase II (CaMKII) is identified as a critical mediator linking cellular calcium dysregulation to pathological cardiac remodeling.
Purpose of the Study:
- To elucidate the multifaceted role of CaMKII in the context of ischaemia and reperfusion injury.
- To explore the potential of targeting CaMKII as a therapeutic strategy for improving outcomes in patients with ischaemic heart disease.
Main Methods:
- The study reviews existing literature on CaMKII's involvement in cardiomyocyte calcium handling and its impact on cardiac function during ischaemia and reperfusion.
- Analysis of CaMKII's activation pathways, downstream targets, and its influence on cellular calcium dynamics, mitochondrial function, and cell survival.
Main Results:
- CaMKII activation during reperfusion exacerbates calcium leak, promotes arrhythmias, and contributes to myocyte death.
- Inhibition of CaMKII can enhance functional recovery and reduce cell death, partly by modulating mitochondrial calcium levels.
- Conversely, CaMKII activation may offer beneficial effects, including inotropic support and involvement in cardioprotective signalling pathways.
Conclusions:
- CaMKII exhibits a complex, dual role in ischaemia-reperfusion injury, with both detrimental and potentially beneficial actions.
- Targeting CaMKII presents a promising avenue for therapeutic intervention in surgical reperfusion strategies.
- Further research is needed to fully understand the relationship between CaMKII activation and ischaemia-reperfusion injury to optimize pharmacological approaches.
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.
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