Inhibition of pancreatic stellate cell activation by the hydroxymethylglutaryl coenzyme A reductase inhibitor lovastatin.
Pancreatic stellate cells (PSCs) play a key role in pancreatic fibrosis, a constant feature of chronic pancreatitis. PSC activation occurs in response to profibrogenic mediators such as cytokines and involves proliferation, transition towards a myofibroblastic phenotype and enhanced production of extracellular matrix proteins. Previously, we have shown that PSC activation correlates with the activity of the Ras-Raf-ERK (extracellular signal-regulated kinase) signalling cascade [Gut 51 (2002) 579]. Using a rat culture model of PSCs, we have now evaluated the effects of lovastatin, a hydroxymethylglutaryl coenzyme A reductase inhibitor that interferes with protein isoprenylation, on PSC viability and activation as well as on signalling through Ras proteins. Apoptotic cells were detected applying the TUNEL assay. Proliferation of PSCs was quantitated using the bromodeoxyuridine DNA incorporation assay. Expression of alpha-smooth muscle actin (an indicator of the myofibroblastic phenotype), ERK activation and membrane translocation of the Ras superfamily member RhoA were analysed by immunoblotting. Lovastatin inhibited serum- and platelet-derived growth factor-stimulated PSC proliferation in a dose-dependent manner. At drug concentrations above the level required for growth inhibition, a strong increase of apoptotic cells was observed. Furthermore, lovastatin inhibited induction of alpha-smooth muscle actin expression in the course of primary culture. Immunoblot experiments indicated that lovastatin suppressed both Ras-mediated ERK 1/2 activation and platelet-derived growth factor-induced membrane translocation of RhoA. Together, our data suggest that lovastatin, through the interruption of Ras signalling, interferes with PSC activation. The antifibrotic efficiency of statins should be tested in animal models of chronic pancreatitis.
Jaster
Robert
R
Department of Medicine, Division of Gastroenterology, Medical Faculty, University of Rostock, E.-Heydemann-Str. 6, Germany. jaster@med.uni-rostock.de
Brock
Peter
P
Sparmann
Gisela
G
Emmrich
Jörg
J
Liebe
Stefan
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008148:Lovastatin / Q000494:pharmacology*; D008297:Male; D010179:Pancreas / Q000166:cytology* / Q000187:drug effects; D010195:Pancreatitis / Q000503:physiopathology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010982:Platelet-Derived Growth Factor; D008148:Lovastatin