Requirement for Ca2+/calmodulin–dependent kinase II in the transition from pressure overload–induced cardiac hypertrophy to heart failure in mice

Abstract

Ca 2+ /calmodulin-dependent kinase II (CaMKII) has been implicated in cardiac hypertrophy and heart failure. We generated mice in which the predominant cardiac isoform, CaMKIIδ, was genetically deleted (KO mice), and found that these mice showed no gross baseline changes in ventricular structure or function. In WT and KO mice, transverse aortic constriction (TAC) induced comparable increases in relative heart weight, cell size, HDAC5 phosphorylation, and hypertrophic gene expression. Strikingly, while KO mice showed preserved hypertrophy after 6-week TAC, CaMKIIδ deficiency significantly ameliorated phenotypic changes associated with the transition to heart failure, such as chamber dilation, ventricular dysfunction, lung edema, cardiac fibrosis, and apoptosis. The ratio of IP 3 R2 to ryanodine receptor 2 (RyR2) and the fraction of RyR2 phosphorylated at the CaMKII site increased significantly during development of heart failure in WT mice, but not KO mice, and this was associated with enhanced Ca 2+ spark frequency only in WT mice. We suggest that CaMKIIδ contributes to cardiac decompensation by enhancing RyR2-mediated sarcoplasmic reticulum Ca 2+ leak and that attenuating CaMKIIδ activation can limit the progression to heart failure.

Calcium/Calmodulin-Dependent Protein Kinase II Couples Wnt Signaling With Histone Deacetylase 4 and Mediates Dishevelled-Induced Cardiomyopathy

“…18,[25][26][27] Interestingly, in this study, we observed that deletion of CaMKIIδ or CaMKIIγ alone is not sufficient to rescue the phenotype of DVL mice, but simultaneous knockout of CaMKIIδ and CaMKIIγ does rescue the phenotype, indicating that CaMKIIγ, which is not the most highly expressed CaMKII isoform in the heart, may also function after pathological injuries. Therefore, when developing new pharmacological compounds to treat cardiac remodeling, both isoforms of CaMKII δ and γ should be taken into account.…”

Spatiotemporally Distinct Protein Kinase D Activation in Adult Cardiomyocytes in Response to Phenylephrine and Endothelin

“…HDAC subtype-specific inhibition might be a way to resolve this benefit conflict, but targeting upstream of HDACs may hold unique benefits. Along these lines, cardiac-specific deletion of PKD1 (and CaMKII␦ knock-out) limit cardiac remodeling after aortic constriction (5,22) and novel PKD inhibitors have had some success in the prevention of pathological hypertrophy (23)(24)(25) as well as of pancreatic and prostatic cancer growth (17,26). In the heart, a better mechanistic understanding of how cardiomyocyte PKD and CaMK are activated in response to pathogenic neurohumoral stimuli (5-6) is needed to evaluate the therapeutic potential of specific PKD/ CaMKII inhibition.…”

α-Kinase Anchoring Protein αKAP Interacts with SERCA2A to Spatially Position Ca2+/Calmodulin-dependent Protein Kinase II and Modulate Phospholamban Phosphorylation

“…The ability of CaMKII␤ 4 isoform to exist in a complex with ␣KAP and SERCA2a and phosphorylate Thr-17 on PLN suggests that this kinase would serve a physiological role in cardiac muscle function as well. In this regard, recent studies indicate that mice that lack CaMKII␦ C in the myocardium exhibit normal physiological function and pathological response to pressure overload (29). In view of our data on the expression and targeting of CaMKII␤ 4 activity to cardiac SR, we suggest that this CaMKII isoform could substitute for CaMKII␦ C and potentially contribute to normal cardiac biology and the acute response to stress in the CaMKII␦ C null mice (29).…”

“…In this regard, recent studies indicate that mice that lack CaMKII␦ C in the myocardium exhibit normal physiological function and pathological response to pressure overload (29). In view of our data on the expression and targeting of CaMKII␤ 4 activity to cardiac SR, we suggest that this CaMKII isoform could substitute for CaMKII␦ C and potentially contribute to normal cardiac biology and the acute response to stress in the CaMKII␦ C null mice (29). Further, CaMKII␤ 4 can bind glycolytic enzymes and regulate glyceraldehyde-3-phosphate dehydrogenase at the SR and has been implicated in the control of local ATP production to support calcium uptake (13,14).…”

“…Given the diverse emerging role of the AKAPs in cAMP signaling cascades (36), it is conceivable that ␣KAP may provide an analogous scaffold/adaptor for the spatial and temporal control of Ca 2ϩ signaling at distinct subcellular locations. In this regard, the calcium release channel is also a substrate for CaMKII (29), and the potential role of ␣KAP in its targeting and regulation is also under investigation. …”