Inhibition of calcium-calmodulin-dependent kinase II suppresses cardiac fibroblast proliferation and extracellular matrix secretion.
Calcium-calmodulin-dependent protein kinase II (CaMKII) is one of the main protein kinases mediating intracellular Ca changes. It is also involved in the process of cardiac diseases, such as cardiac hypertrophy, but its effects on myocardial fibrosis remain unclear. The present study investigates whether CaMKII is involved in cardiac fibroblast proliferation and extracellular matrix (ECM) secretion induced by angiotensin II (AngII) or electrical field stimulation (EFS) in cultured neonatal rat cardiac fibroblasts. Cardiac fibroblast proliferation was assessed by a cell survival assay (MTT) and manual cell enumeration. Cellular matrix production was demonstrated by matrix metalloproteinases (MMP) 1, 2, 9, and collagen I/III messenger RNA expression, MMP-2, 9 protein expression, and secretion of transforming growth factor beta1 and tumor necrosis factor alpha. Either AngII or EFS promoted cardiac fibroblast proliferation and ECM secretion, while also up-regulating expression of CaMKII deltaB and deltaC. More importantly, CaMKII inhibitors, autocamtide-2-related inhibitory peptide (AIP 5 microM) or KN93 (0.5 microM), suppressed cardiac fibroblast proliferation, inhibited the excretion of transforming growth factor beta1 and tumor necrosis factor alpha, decreased the messenger RNA expression of MMP-1, 2, 9 and collagen I/III, and decreased the protein expression of MMP-2, 9. These results suggest that CaMKII mediates cardiac fibroblast proliferation and ECM secretion induced by either AngII or EFS.
Zhang
Wei
W
Department of Pharmacology, Nantong University Medical College, Nantong, China.
Chen
Dong-Qin
DQ
Qi
Feng
F
Wang
Jing
J
Xiao
Wen-Yan
WY
Zhu
Wei-Zhong
WZ
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001596:Benzylamines / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D004558:Electric Stimulation; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology; D000096926:Benzenesulfonamides
D000804:Angiotensin II; D001596:Benzylamines; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D010455:Peptides; D013449:Sulfonamides; C514527:autocamptide-2-related inhibitory peptide II; C072105:KN 93; D000096926:Benzenesulfonamides