CaMKII: The molecular villain that aggravates cardiovascular disease

Abstract

Pathological remodeling of the myocardium is an integral part of the events that lead to heart failure (HF), which involves altered gene expression, disturbed signaling pathways and altered Ca²⁺ homeostasis and the players involved in this process. Of particular interest is the chronic activation of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) isoforms in heart, which further aggravate the injury to myocardium. Expression and activity of CaMKII have been found to be elevated in various conditions of stressed myocardium and in different heart diseases in both animal models as well as heart patients. CaMKII is a signaling molecule that regulates many cellular pathways by phosphorylating several proteins involved in excitation-contraction coupling and relaxation events in heart, cardiomyocyte apoptosis, transcriptional activation of genes related to cardiac hypertrophy, inflammation, and arrhythmias. CaMKII is activated by reactive oxygen species (ROS), which are elevated under conditions of ischemia-reperfusion injury and in a cyclical manner, CaMKII in turn elevates ROS production. Both ROS and activated CaMKII increase Ca-induced Ca release from sarcoplasmic reticulum, which leads to cardiomyocyte membrane depolarization and arrhythmias. These CaMKII-mediated changes in heart ultimately culminate in dysfunctional myocardium and HF. Genetic studies in animal models clearly demonstrated that inactivation of CaMKII is protective against a variety of stress induced cardiac dysfunctions. Despite significant leaps in understanding the structural details of CaMKII, which is a very complicated and multimeric modular protein, currently there is no specific and potent inhibitor of this enzyme, that can be developed for therapeutic purposes.

Keywords: CaMKII; RyR2; SERCA; arrhythmias; cardiac dysfunction; cardiac hypertrophy; heart failure.

Figure 1.

Domain structure of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) monomer and potential regulatory sites. A schematic showing the CaMKII monomer with catalytic, regulatory and association domains. Catalytic domain function is normally obscured by the regulatory domain. Association domain is instrumental in forming the holoenzyme that consists of 12 monomers. Post-translational modifications by different stress stimuli and neurohormonal signaling at the indicated sites in the regulatory domain lead to sustained activation of CaMKII by relieving the catalytic domain.

Figure 2.

Mechanisms of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) dependent cardiac dysfunction. Increase in intracellular Ca²⁺ through L-type Ca²⁺ channels, leads to CaMKIIδ activation via Ca²⁺/Calmodulin (CaM) in cardiomyocyte. Activated CaMKIIδ contributes to elevated reactive oxygen species (ROS), which can also arise from other stress stimuli, themselves can activate CaMKIIδ, resulting in a vicious cycle of CaMKIIδ activation. Both the phosphorylation mediated by CaMKIIδ and ROS-mediated oxidation of the type 2-ryanodine receptor (RyR2) in sarcoplasmic reticulum (SR) lead to enhanced SR Ca²⁺ load and in turn, cause SR Ca²⁺ leak followed by the re-uptake of Ca²⁺ by SERCA into SR. This triggers sodium/calcium exchanger (NCX)-dependent depolarizing current (transient inward current), which contributes to arrhythmia. Activated CaMKIIδ also elevates transcription of cardiac hypertrophy genes, which culminates in cardiac hypertrophy and thus dysfunction of heart. Activated CaMKII is known to trigger cardiomyocyte apoptosis program, leading to loss of cardiomyocytes and thus damaged myocardium. All these events resulting from CaMKII activation, contribute to failure of the heart.