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Yang JI, Yoon JH, Bang YJ, Lee SH, Lee SM, Byun HJ, Myung SJ, Kim W, Lee HS: Synergistic Anti-Fibrotic Efficacy of Statin and Protein Kinase C Inhibitor in Hepatic Fibrosis. Am J Physiol Gastrointest Liver Physiol. 2009 Nov 12.
Statin has anti-fibrotic efficacy in human fibrosing diseases, such as pulmonary and renal fibrosis, and is therefore implicated in hepatic fibrosis. However, statin can also activate protein kinase C (PKC), which augments hepatic fibrogenesis and is thereby likely to reduce the anti-fibrotic efficacy of statin. This study was designed to explore the hypothesis that simultaneous treatment with statin and PKC inhibitor may synergistically enhance anti-fibrotic efficacy in hepatic fibrosis. Hepatic fibrosis models were established in BALB/c mouse by intraperitoneal injection of carbon tetrachloride or thioacetamide for 6 weeks. Pravastatin and enzastaurin (PKC inhibitor) were administered by gavage for 5 weeks. Cellular apoptosis was explored using DAPI or TUNEL staining and immunoblot analysis. Hepatic fibrosis and HSC activation were assessed by morphometric analysis of histological findings and immunohistochemistry for alpha-smooth muscle actin. In vitro, the addition of PKC inhibitor significantly increased statin-induced LX-2 cell apoptosis by enhancing the activation of mitochondrial apoptotic signals. TUNEL-positive HSCs were significantly increased in mice treated with statin+PKC inhibitor compared to those in control or single compound-treated mice. The percentage of area occupied by activated HSCs and the extent of collagen deposition were significantly decreased in mice treated with statin+PKC inhibitor compared to those in control or statin-treated mice. In conclusion, simultaneous treatment with statin and PKC inhibitor synergistically enhanced the anti-fibrotic efficacy in both in vitro and in vivo models of hepatic fibrosis and may therefore have therapeutic implication for reducing hepatic fibrosis. |
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