Gut Liver.  2012 Apr;6(2):262-269.

The Effects of Combined Treatment with an HMG-CoA Reductase Inhibitor and PPARgamma Agonist on the Activation of Rat Pancreatic Stellate Cells

• Lee BJ
• Lee HS
• Kim CD
• Jung SW
• Seo YS
• Kim YS
• Jeen YT
• Chun HJ
• Um SH
• Lee SW
• Choi JH
• Ryu HS

Abstract

BACKGROUND/AIMS
Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) and peroxisome proliferator-activated receptor gamma (PPARgamma) ligands can modulate cellular differentiation, proliferation, and apoptosis through various pathways. It has been shown that HMG-CoA reductase inhibitors and PPARgamma agonists separately inhibit pancreatic stellate cell (PaSC) activation. We studied the effects of a combination of both types of drugs on activated PaSCs via platelet-derived growth factor (PDGF), which has not previously been reported. The present study was performed to elucidate the underlying mechanisms of these effects by focusing on the impact of the signaling associated with cell-cycle progression.
METHODS
Primary cultures of rat PaSCs were exposed to simvastatin and troglitazone. Proliferation was quantified using the BrdU method, and cell-cycle analysis was performed using a fluorescent activated cell sorter. The protein expression levels of smooth muscle actin (SMA), extracellular signal-regulated kinase (ERK), and a cell cycle machinery protein (p27Kip1) were investigated using Western blot analysis.
RESULTS
Simvastatin reversed the effects of PDGF on cell proliferation in a dose-dependent manner. The combination of a low concentration of simvastatin (1 mM) and troglitazone (10 mM) synergistically reversed the effects of PDGF on cell proliferation but had no effect on cell viability. The expression of a-SMA was markedly attenuated by combining the two drugs, which blocked the cell cycle beyond the G0/G1 phase by reducing the levels of phosphorylated ERK and reversed the expression of p27Kip1 interrupted by PDGF.
CONCLUSIONS
Simvastatin and troglitazone synergistically inhibited cell proliferation in activated PaSCs by blocking the cell cycle beyond the G0/G1 phase. This inhibition was due to the synergistic modulation of the ERK pathway and the cell cycle machinery protein p27Kip1.

Keyword

HMG-CoA reductase inhibitor; PPARgamma agonist; Pancreatic stellate cells; Synergism

MeSH Terms

Actins
Acyl Coenzyme A
Animals
Apoptosis
Blotting, Western
Bromodeoxyuridine
Cell Cycle
Cell Proliferation
Cell Survival
Chromans
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Ligands
MAP Kinase Signaling System
Muscle, Smooth
Oxidoreductases
Pancreatic Stellate Cells
Phosphotransferases
Platelet-Derived Growth Factor
PPAR gamma
Rats
Simvastatin
Thiazolidinediones
Actins
Acyl Coenzyme A
Bromodeoxyuridine
Chromans
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Ligands
Oxidoreductases
PPAR gamma
Phosphotransferases
Platelet-Derived Growth Factor
Simvastatin
Thiazolidinediones