Effect of HMG-CoA reductase inhibitors on proliferation and protein synthesis by rat hepatic stellate cells.
OBJECTIVE
3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors called statins, have besides their cholesterol-lowering function, therapeutic value in conditions such as neo-angiogenesis and atherosclerosis. We investigated the effect of two statins on the proliferation rate and protein steady state levels of hepatic stellate cells (HSC).


METHODS
Cellular DNA synthesis under the influence of statins and/or platelet derived growth factor (PDGF) and mevalonate was evaluated by measuring BrdU incorporation. Synthesis of collagens type I, III, IV and fibronectin was quantified by ELISA. Additionally, we examined the influence of simvastatin on isoprenylation of Ras and RhoA proteins.


RESULTS
Lovastatin and simvastatin induced a dose-dependent inhibition of the proliferation rate of HSC. Subsequent addition of PDGF and/or mevalonate, after long-term exposure of simvastatin to HSC, did not reverse simvastatins' antiproliferative effect. Lovastatin and simvastatin reduced the protein steady state level of collagens type I (-40%), III (-45%) and IV (-27%). Membrane bound Ras steady state levels decreased under the influence of simvastatin. Membrane bound RhoA remained unaltered, whereas, cytosolic RhoA protein level was strongly reduced.


CONCLUSIONS
Our data showed that lovastatin and simvastatin inhibited HSC proliferation and collagen steady state levels by mechanisms independent of their lipid reducing activities.
Rombouts
Krista
K
Laboratory for Molecular Liver Cell Biology, Faculty of Medicine and Pharmacy, Free University of Brussels (VUB), Laarbeeklaan 103, 1090 Brussels-Jette, Belgium. krom@cyto.vub.ac.be
Kisanga
Elton
E
Hellemans
Karine
K
Wielant
Annemie
A
Schuppan
Detlef
D
Geerts
Albert
A
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D024042:Collagen Type I / Q000096:biosynthesis*; D024061:Collagen Type III / Q000096:biosynthesis; D024141:Collagen Type IV / Q000096:biosynthesis; D005353:Fibronectins / Q000096:biosynthesis; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D008099:Liver / Q000166:cytology* / Q000378:metabolism; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000378:metabolism; D008148:Lovastatin / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D010641:Phenotype; D051381:Rats; D017208:Rats, Wistar; D019821:Simvastatin / Q000494:pharmacology; D018631:ras Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D024042:Collagen Type I; D024061:Collagen Type III; D024141:Collagen Type IV; D005353:Fibronectins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008565:Membrane Proteins; D008148:Lovastatin; D019821:Simvastatin; D018631:ras Proteins; D020742:rhoA GTP-Binding Protein