Ca²⁺/calmodulin-dependent protein kinase II mediates platelet-derived growth factor-induced human hepatic stellate cell proliferation.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Division of Gastroenterology and Hepatology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan 430060, China.
An
A
Ping
Tian
T
Yihao
Dai
D
Jingxing
Chen
C
Minkai
Luo
L
Hesheng
D001596:Benzylamines / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D055785:Gene Knockdown Techniques; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology; D014162:Transfection; D000096926:Benzenesulfonamides
D001596:Benzylamines; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D004247:DNA; D010982:Platelet-Derived Growth Factor; D034741:RNA, Small Interfering; D013449:Sulfonamides; C072105:KN 93; D000096926:Benzenesulfonamides