Synergistic antifibrotic efficacy of statin and protein kinase C inhibitor in hepatic fibrosis.
Statin has antifibrotic 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 antifibrotic efficacy of statin. This study was designed to explore the hypothesis that simultaneous treatment with statin and PKC inhibitor may synergistically enhance antifibrotic efficacy in hepatic fibrosis. Hepatic fibrosis models were established in BALB/c mice by intraperitoneal injection of carbon tetrachloride or thioacetamide for 6 wk. Pravastatin and enzastaurin (PKC inhibitor) were administered by gavage for 5 wk. Cellular apoptosis was explored using 4',6-diamidino-2-phenylindole or terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end-labeling (TUNEL) staining and immunoblot analysis. Hepatic fibrosis and hepatic stellate cell (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 with 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 with those in control or statin-treated mice. In conclusion, simultaneous treatment with statin and PKC inhibitor synergistically enhanced the antifibrotic efficacy in both in vitro and in vivo models of hepatic fibrosis and may therefore have therapeutic implication for reducing hepatic fibrosis.
Yang
Jong In
JI
Prof. of Internal Medicine, Seoul National Univ. Coll. of Medicine, 28 Yungun-dong, Jongno-gu, Seoul 110-744, Korea.
Yoon
Jung-Hwan
JH
Bang
Yung-Jue
YJ
Lee
Sung-Hee
SH
Lee
Soo-Mi
SM
Byun
Hee Jin
HJ
Myung
Sun-Jung
SJ
Kim
Won
W
Lee
Hyo-Suk
HS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002251:Carbon Tetrachloride / Q000633:toxicity; D002461:Cell Line, Transformed; D004195:Disease Models, Animal; D004357:Drug Synergism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000187:drug effects; D009929:Organ Size / Q000187:drug effects; D017035:Pravastatin / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D013853:Thioacetamide / Q000633:toxicity
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D047428:Protein Kinase Inhibitors; D013853:Thioacetamide; D002251:Carbon Tetrachloride; D011493:Protein Kinase C; D017035:Pravastatin; C504878:enzastaurin