12-O-tetradecanoylphorbol-13-acetate Reduces Activation of Hepatic Stellate Cells by Inhibiting the Hippo Pathway Transcriptional Coactivator YAP

卷:12

Article

关键词: PROTEIN-KINASE-C;    NF-KAPPA-B;    GROWTH-FACTOR;    HEART-FAILURE;    TGF-BETA;    PHARMACOLOGICAL INHIBITION;    COLLAGEN-SYNTHESIS;    CARDIAC FIBROSIS;    GENE-EXPRESSION;    DOWN-REGULATION;   

DOI  :  10.3390/cells12010091

来源: SCIE

【 摘 要 】

Although protein kinase C (PKC) regulates various biological activities, including cell proliferation, differentiation, migration, tissue remodeling, gene expression, and cell death, the antifibrotic effect of PKC in myofibroblasts is not fully understood. We investigated whether 12-O-tetradecanoylphorbol-13-acetate (TPA), a PKC activator, reduced the activation of hepatic stellate cells (HSCs) and explored the involvement of the Hippo pathway transcriptional coactivator YAP. We analyzed the effect of TPA on the proliferation and expression of alpha-smooth muscle actin (SMA) in the LX-2 HSC line. We also analyzed the phosphorylation of the Hippo pathway molecules YAP and LATS1 and investigated YAP nuclear translocation. We examined whether Go 6983, a pan-PKC inhibitor, restored the TPA-inhibited activities of HSCs. Administration of TPA decreased the growth rate of LX-2 cells and inhibited the expression of alpha-SMA and collagen type I alpha 1 (COL1A1). In addition, TPA induced phosphorylation of PKC delta, LATS1, and YAP and inhibited the nuclear translocation of YAP compared with the control. These TPA-induced phenomena were mostly ameliorated by Go 6983. Our results indicate that PKC delta exerts an antifibrotic effect by inhibiting the Hippo pathway in HSCs. Therefore, PKC delta and YAP can be used as therapeutic targets for the treatment of fibrotic diseases.