The effect of Ras inhibition on the proliferation, apoptosis and matrix metalloproteases activity in rat hepatic stellate cells.
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.
Zvibel
Isabel
I
Gastroenterology Institute, Tel Aviv Sourasky Medical Center, Weizmann 6, Tel Aviv, Israel. isab@tasmc.health.gov.il
Bar-Zohar
Dan
D
Kloog
Yoel
Y
Oren
Ran
R
Reif
Shimon
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D018929:Cell Culture Techniques; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D024042:Collagen Type I / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005204:Farnesol / Q000031:analogs & derivatives* / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects* / Q000502:physiology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051381:Rats; D012459:Salicylates / Q000494:pharmacology*; D018631:ras Proteins / Q000037:antagonists & inhibitors*
D024042:Collagen Type I; D004791:Enzyme Inhibitors; D012459:Salicylates; C093323:farnesylthiosalicylic acid; D005204:Farnesol; D020782:Matrix Metalloproteinases; D018631:ras Proteins