CaMKIIdelta overexpression in hypertrophy and heart failure: cellular consequences for excitation-contraction coupling

Abstract

Ca/calmodulin-dependent protein kinase IIdelta (CaMKIIdelta) is the predominant isoform in the heart. During excitation-contraction coupling (ECC) CaMKII phosphorylates several Ca-handling proteins including ryanodine receptors (RyR), phospholamban, and L-type Ca channels. CaMKII expression and activity have been shown to correlate positively with impaired ejection fraction in the myocardium of patients with heart failure and CaMKII has been proposed to be a possible compensatory mechanism to keep hearts from complete failure. However, in addition to these acute effects on ECC, CaMKII was shown to be involved in hypertrophic signaling, termed excitation-transcription coupling (ETC). Thus, animal models have shown that overexpression of nuclear isoform CaMKIIdeltaB can induce myocyte hypertrophy. Recent study from our laboratory has suggested that transgenic overexpression of the cytosolic isoform CaMKIIdeltaC in mice causes severe heart failure with altered intracellular Ca handling and protein expression leading to reduced sarcoplasmic reticulum (SR) Ca content. Interestingly, the frequency of diastolic spontaneous SR Ca release events (or opening of RyR) was greatly enhanced, demonstrating increased diastolic SR Ca leak. This was attributed to increased CaMKII-dependent RyR phosphorylation, resulting in increased and prolonged openings of RyR since Ca spark frequency could be reduced back to normal levels by CaMKII inhibition. This review focuses on acute and chronic effects of CaMKII in ECC and ETC. In summary, CaMKII overexpression can lead to heart failure and CaMKII-dependent RyR hyperphosphorylation seems to be a novel and important mechanism in ECC due to SR Ca leak which may be important in the pathogenesis of heart failure.

Cardiomyocytes with disrupted CFTR function require CaMKII and Ca2+‐activated Cl− channel activity to maintain contraction rate

“…These findings are of particular interest, since cardiac myocytes with increased CaMKII expression or activity are prone to pathological cardiac conditions. Calcium/calmodulin‐dependent kinase II has been linked to heart failure; hearts from mice with heart failure have increased expression of CaMKIIδ, and overexpression of CaMKII causes heart failure in mice (Hoch et al 1999; Maier, 2005). In addition, increased CaMKII activity may lead to prolonged action potential duration and cause long QT syndrome by increasing late‐inactivating or slowly inactivating Na + currents (Bers, 2008).…”

Increased Expression of Calcium/Calmodulin-Dependent Protein Kinase Type II Subunit Delta after Rat Traumatic Brain Injury

“…Important functions of CaMKII include the control of neurotransmitter release and the mediation of stimulus-induced gene expression (Moreno-Delgado et al 2009;Shen et al 2010). CaMKIIδ, by the very nature of its core function as a kinase, is a multifunctional signaling protein that regulates numerous physiological processes including cellular differentiation (Donai et al 2000;Ju et al 2004;Banno et al 2008;Han et al 2011;Mouton-Liger et al 2011), ion channel function (Wagner et al 2011), arrhythmogenesis during atrial fibrillation (Tobimatsu and Fujisawa 1989;Qin et al 2011), modulating inflammatory and proliferative responses (Currie et al 2011), vascular smooth muscle proliferation (House et al 2007;House and Singer 2008;Li et al 2011), heart failure (Zhang et al 2004;Maier 2005;Rokita et al 2011), and pathological processes such as apoptosis induced by ischemia/reperfusion injury in cardiomyoctyes (Ma et al 2009;Wang et al 2010). Knowledge of the participation of CaMKIIδ in cell physiology and apoptotic pathways in central nervous system is limited.…”

Rescue of cardiac failing and remodelling by inhibition of protein phosphatase 1γis associated with suppression of the alternative splicing factor-mediated splicing of Ca2+/calmodulin-dependent protein kinase δ

“…As the splicing product of CaMKII, such as CaMKII δ C, was well‐known to mediate the development of cardiac hypertrophy, we next tested whether overexpression or inhibition of PP1 γ can influence the splicing of CaMKII δ in chronic hypertrophic heart . As anticipated, AAC stress upregulated the production of CaMKII δ C and simultaneously decreased the production of δ B in hypertrophic hearts (Fig.…”