Ca2+/calmodulin-dependent protein kinase IIdelta orchestrates G-protein-coupled receptor and electric field stimulation-induced cardiomyocyte hypertrophy.

Abstract

1. G-Protein-coupled receptors (GPCR) and electrical field stimulation (EFS) regulate cardiac function and pathological remodelling, including cardiac hypertrophy. Cardiac Ca(2+)/calmodulin-dependent protein kinase (CaMK) IIdelta expression and activity are altered in cardiac hypertrophy and heart failure. The aim of the present study was to determine the effects of CaMKIIdelta 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, [(3)H]-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 CaMKIIdelta. 3. Cardiomyocyte hypertrophy was inhibited by the CaMKII inhibitors KN93 and AIP and by overexpression of dominate negative CaMKIIdelta, but was potentiated by overexpression of wild-type CaMKIIdeltaB or CaMKIIdeltaC. 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 CaMKIIdeltaB and CaMKIIdeltaC 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.

• Authors: Wei Zhang, Feng Qi, Dong-Qin Chen, Wen-Yan Xiao, Jing Wang, Wei-Zhong Zhu
• Journal: Clinical and experimental pharmacology & physiology (Clin Exp Pharmacol Physiol) Vol. 37 Issue 8 Pg. 795-802 (Aug 2010) ISSN: 1440-1681 [Electronic] Australia
• PMID: 20374261 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CaMKII inhibitor AIP
• Calcium-Binding Proteins
• Peptides
• Protein Kinase Inhibitors
• Receptors, G-Protein-Coupled
• phospholamban
• Angiotensin II
• Calcium-Calmodulin-Dependent Protein Kinase Type 2
• Camk2d protein, rat
• Leucine

Topics

• Adenoviridae (genetics)
• Angiotensin II (pharmacology)
• Animals
• Animals, Newborn
• Blotting, Western
• Calcium-Binding Proteins (metabolism)
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (antagonists & inhibitors, physiology)
• Cell Size (drug effects)
• Cells, Cultured
• Electric Stimulation
• Immunohistochemistry
• Leucine (metabolism)
• Myocytes, Cardiac (drug effects, physiology, ultrastructure)
• Peptides (metabolism)
• Phosphorylation
• Protein Kinase Inhibitors (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptors, G-Protein-Coupled (physiology)
• Reverse Transcriptase Polymerase Chain Reaction