The Effect of Ras Inhibition on the Proliferation, Apoptosis and Matrix Metalloproteases Activity in Rat Hepatic Stellate Cells |
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Authors: | Isabel Zvibel Dan Bar-Zohar Yoel Kloog Ran Oren Shimon Reif |
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Institution: | (1) Gastroenterology Institute, Tel Aviv Sourasky Medical Center, Weizmann 6, Tel Aviv, Israel;(2) Department of Surgery B, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel;(3) Department of Neurobiochemistry, Tel Aviv University, Tel Aviv, Israel;(4) Department of Pediatric Gastroenterology, Dana Children Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel |
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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 IC50 of FTS that inhibited PDGF-induced proliferation was 15 μM. 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 TGFβ1.
We observed increased activity of MMP-9 and MMP-2 induced by FTS in combination with PDGF or TGFβ. FTS, alone or in the presence
of PDGF and TGFβ, 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. |
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Keywords: | Hepatic stellate cells Liver fibrosis Ras inhibition Metalloproteases |
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