Ca^sup 2+^/Calmodulin-Dependent Protein Kinase II Mediates Platelet-Derived Growth Factor-Induced Human Hepatic Stellate Cell Proliferation

• Published in: Digestive diseases and sciences Vol. 57; no. 4; p. 935
• Main Authors: Ping, An, Yihao, Tian, Jingxing, Dai, Minkai, Chen, Hesheng, Luo
• Format: Journal Article
• Language: English
• Published: New York Springer Nature B.V 01.04.2012
• ISSN: 0163-2116; 1573-2568
• DOI: 10.1007/s10620-011-2014-2

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^sup 2+^ signal is involved in PDGF pathways. We showed previously for the first time that Ca^sup 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.[PUBLICATION ABSTRACT]