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Proliferation and activation of myofibroblastic hepatic stellate cells (HSCs) in response to growth factors is essential for the development of liver fibrosis. As one of the most potent factors, platelet-derived growth factor (PDGF) activates intracellular signals and contributes to sustained HSCs activation. Growing evidence has suggested that the Ca(2+) signal is involved in PDGF pathways. We showed previously for the first time that Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is essential for human HSC proliferation. The inhibition of CaMKII by its specific inhibitor, KN-93, significantly decreased the HSC growth and increased expression of cell cycle suppressive regulators P53 and P21. In the present study, we investigated the role of CaMKII in PDGF-induced HSC proliferation and underlying mechanisms. We confirmed that in human HSCs, PDGF significantly increased CaMKII mRNA levels, protein expression, and phosphorylation. The interruption of CaMKII by KN-93, specific inhibitory peptide (AIP), or specific CaMKII knockdown by its siRNA not only attenuated PDGF-induced HSC proliferation but also ERK1/2 phosphorylation. However, CaMKII had no effect on JNK phosphorylation. In addition, inhibitors of ERK1/2 (PD98059) and JNK (SP600125) did not affect CaMKII expression. Interruption of CaMKII-ERK cascade, not JNK signal, inhibited PDGF-induced HSC proliferation. We confirmed that CaMKII mediated PDGF-induced human HSC proliferation through ERK1/2 but not the JNK mechanism. Our study shed light on CaMKII as a crucial signal in PDGF-activated HSCs and a potential therapeutic point in hepatic fibrosis.

Citation

An Ping, Tian Yihao, Dai Jingxing, Chen Minkai, Luo Hesheng. Ca²⁺/calmodulin-dependent protein kinase II mediates platelet-derived growth factor-induced human hepatic stellate cell proliferation. Digestive diseases and sciences. 2012 Apr;57(4):935-42

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PMID: 22215519

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