The Effect of Ras Inhibition on the Proliferation, Apoptosis and Matrix Metalloproteases Activity in Rat Hepatic Stellate Cells

Abstract

In vivo inhibition of Ras by its antagonist farnesylthiosalicylic acid (FTS) prevents and reverses liver fibrosis in a rat model. In this study we showed the in vitro effects of Ras inhibition in a rat hepatic stellate cell line, HSC-T6. The IC(50) of FTS that inhibited PDGF-induced proliferation was 15 microM. FTS, by itself or in combination with PDGF, induced a three- to fivefold increase in the number of apoptotic stellate cells but did not induce apoptosis in cells cultured with TGFbeta1. We observed increased activity of MMP-9 and MMP-2 induced by FTS in combination with PDGF or TGFbeta. FTS, alone or in the presence of PDGF and TGFbeta, reduced collagen I mRNA expression. In conclusion, the in vivo amelioration of liver fibrosis by FTS may be explained by its ability to inhibit hepatic stellate cell proliferation, induce apoptosis and MMP-2 and MMP-9 activity, and decrease collagen I expression.

Prevention of Induced Colitis in Mice by the Ras Antagonist Farnesylthiosalicylic Acid

“…In a model of liver cirrhosis induced by thioacetamide in rats, FTS had preventive qualities by inhibiting hepatic stellate cell activation and proliferation [20]. In the same model, FTS was found to be an effective treatment, partially reversing liver cirrhosis by reducing collagen secretion and up-regulating metalloproteinase activity [19,27]. In the current study, we found that FTS had a beneficial effect on the inflammatory process of experimentally induced colitis in mice.…”

Transcriptional analysis identifies key genes involved in metabolism, fibrosis/tissue repair and the immune response against Fasciola hepatica in sheep liver

“…Additional examples are the up-regulation in infected animals of genes encoding the TGF-β1 and its Induced Transcript 1 (TGF-β1I1) as well as the chemokines CCL3 and CCL4. In addition to its roles in regulating T-cell differentiation (see above), TGF-β1 is also relevant in fibrosis [ 99 - 102 ]. CCL3 and CCL4 are expressed by a number of cell types, including activated B cells, monocytes, mast cells, fibroblasts and epithelial cells [ 103 ].…”

Differential role of YiGanKang Decoction in IL-1β induction of IL-1RI and AP-1 in rat hepatic stellate cell

“…HSCs, the main source of ECM, play important roles in the formation of hepatic fibrosis (Fischer et al, 2001;Issa et al, 2001;Vincent et al, 2001;Zvibel et al, 2008). We recently demonstrated that YiGanKang Decoction inhibit liver fibrosis via HSCs inhibition (Yao et al, 2002aWang et al, 2005;Yao and Lv, 2005).…”