Ca2+/Calmodulin-Dependent Protein Kinase Ii Delta Orchestrates G-Protein-Coupled Receptor And Electric Field Stimulation-Induced Cardiomyocyte Hypertrophy

P>1. G-Protein-coupled receptors (GPCR) and electrical field stimulation (EFS) regulate cardiac function and pathological remodelling, including cardiac hypertrophy. Cardiac Ca2+/calmodulin-dependent protein kinase (CaMK) II delta expression and activity are altered in cardiac hypertrophy and heart failure. The aim of the present study was to determine the effects of CaMKII delta isoforms on neonatal rat cardiomyocyte hypertrophy induced by GPCR and EFS.2. Cardiac hypertrophy was induced by angiotensin II, phenylephrine or EFS and was confirmed by increases in cell volume, [3H]-leucine incorporation, sarcomere assembly and mRNA expression of atrial natriuretic factor and beta-myosin heavy chain. The effects of the CaMKII inhibitors KN93 and autocamtide 2-related inhibitory peptide (AIP) on cardiomyocyte hypertrophy were investigated, as was the effect of overexpression of dominate negative CaMKII delta.3. Cardiomyocyte hypertrophy was inhibited by the CaMKII inhibitors KN93 and AIP and by overexpression of dominate negative CaMKII delta, but was potentiated by overexpression of wild-type CaMKII delta B or CaMKII delta C. Activation of CaMKII by GPCR agonists or EFS was inhibited by the CaMKII inhibitors.4. The GPCR agonists and EFS synergistically activated CaMKII and upregulated CaMKII delta B and CaMKII delta C mRNA expression and protein synthesis. All these effects were abolished by the CaMKII inhibitors.5. The findings of the present study indicate that CaMKII orchestrates additive prohypertrophic factors between GPCR agonists and EFS. Thus, CaMKII may be a useful target in the clinical treatment of hypertrophy and cardiac remodelling.