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Digestive Diseases and Sciences
Published in: Digestive Diseases and Sciences 4/2012

01-04-2012 | Original Article

Ca2+/Calmodulin-Dependent Protein Kinase II Mediates Platelet-Derived Growth Factor-Induced Human Hepatic Stellate Cell Proliferation

Authors: An Ping, Tian Yihao, Dai Jingxing, Chen Minkai, Luo Hesheng

Published in: Digestive Diseases and Sciences | Issue 4/2012

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Abstract

Background and Aim

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 Ca2+ signal is involved in PDGF pathways. We showed previously for the first time that Ca2+/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.

Methods

In the present study, we investigated the role of CaMKII in PDGF-induced HSC proliferation and underlying mechanisms.

Results

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.

Conclusion

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.
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Metadata
Title
Ca2+/Calmodulin-Dependent Protein Kinase II Mediates Platelet-Derived Growth Factor-Induced Human Hepatic Stellate Cell Proliferation
Authors
An Ping
Tian Yihao
Dai Jingxing
Chen Minkai
Luo Hesheng
Publication date
01-04-2012
Publisher
Springer US
Published in
Digestive Diseases and Sciences / Issue 4/2012
Print ISSN: 0163-2116
Electronic ISSN: 1573-2568
DOI
https://doi.org/10.1007/s10620-011-2014-2

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