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  • br CaMKII and heart failure progression

    2019-04-16


    CaMKII and heart failure progression CaMKII is a multifunctional serine–threonine kinase, phosphorylating target proteins. Under resting conditions, CaMKII is inactive. A rise in intracellular Ca2+ stimulates binding of Ca2+ to calmodulin (CaM), a ubiquitous Ca2+-binding protein. The Ca2+/CaM complex activates CaMKII (Ca2+/CaM-dependent activation). With a sustained increase in Ca2+/CaM or reactive oxygen species (ROS), CaMKII transitions into a Ca2+/CaM-autonomous active enzyme after autophosphorylation at Thr286 or oxidation at Met281/282 (Ca2+/CaM-independent activation) [46,47]. This activation is maintained under normal Ca2+ concentrations, a feature that has been regarded to be similar to a “memory” molecule [47]. Autophosphorylated and/or oxidized CaMKII that become constitutively active participate in the disease pathway by phosphorylating protein targets for excitation–contraction coupling and cell survival, including ion p coumaric acid and Ca2+-handling proteins, and transcription factors that drive hypertrophic and inflammatory gene expression. CaMKII is now linked to the pathophysiology of a variety of cardiac diseases including HF, myocardial infarction, ischemia/reperfusion and cardiac arrhythmias, most of which have been demonstrated by Anderson et al. and reviewed in their excellent articles [45,47–49]. The expression and activity of CaMKII are increased in human and animals with HF. CaMKII-overexpressing mice died prematurely with HF phenotype [39–41]. Deletion of CaMKIIδ, a predominant cardiac isoform, prevented transition from pressure overload-induced hypertrophy to HF in mice [50]. CaMKII triggers diverse, maladaptive cellular events essential to HF development, including hypertrophy, inflammation, and cell death. Excessive CaMKII activates hypertrophic genes by phosphorylating class II histone deacetylases and by derepressing myocyte enhancer factor 2-dependent transcription [51]. CaMKII mediates NF-κB activation to activate proinflammatory genes after myocardial infarction [31] and ischemia/reperfusion [34]. Genetic CaMKII inhibition attenuates adverse remodeling and protects against HF after myocardial infarction in mice [31]. Excessive CaMKII also causes mitochondrial Ca2+ dysregulation and activates the cell death pathway [49]. An increase in mitochondrial Ca2+ concentrations secondary to cytosolic Ca2+ overload depolarizes the membrane potential across the inner membrane potential (Δψm), produces ROS, and activates mitochondrial permeability transition pore (mPTP) opening, followed by the subsequent release of apoptosis-related proteins into the cytosol [49]. CaMKII promotes Δψm depolarization and mPTP opening in permeabilized rat myocytes [52]. A recent study has found that CaMKII phosphorylates mitochondrial Ca2+ uniporter, a mitochondrial Ca2+ entry channel, resulting in increased inward current into the mitochondria. Mitochondrion-delimited CaMKII inhibition prevented mPTP opening and Δψm depolarization and diminished mitochondrial disruption and cell death in response to ischemic/reperfusion injury in mice [53]. The effect of CaMKII on ion channels contributes to aberrant intracellular Ca2+ homeostasis in HF. CaMKII-dependent hyperphosphorylation of RyR2 increases inappropriate diastolic Ca2+ release from SR that promotes HF (because of loss of SR Ca2+ load) and arrhythmogenic delayed afterdepolarizations. Pharmacological CaMKII inhibition reduces the phosphorylation levels of RyR2 at both Ser2809 (PKA/CaMKII phosphorylation site) and Ser2815 (CaMKII site) and improves contractility along with reduced SR Ca2+ leak and increased SR Ca2+ stores in failing human myocardium [54]. Mice with constitutively phosphorylated RyR2 that can be attributed to mutant S2814D have RyR2-mediated SR Ca2+ leak and develop late onset cardiomyopathy [55]. Moreover, knock-in mice with an inactivated Ser2814 phosphorylation site are protected from HF development after transverse aortic constriction [56].