The Effects of Combined Treatment with an HMG-CoA Reductase Inhibitor and PPARgamma Agonist on the Activation of Rat Pancreatic Stellate Cells.
- Author:
Beom Jae LEE
1
;
Hong Sik LEE
;
Chang Duck KIM
;
Sung Woo JUNG
;
Yeon Seok SEO
;
Yong Sik KIM
;
Yoon Tae JEEN
;
Hoon Jai CHUN
;
Soon Ho UM
;
Sang Woo LEE
;
Jai Hyun CHOI
;
Ho Sang RYU
Author Information
1. Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea. hslee@korea.ac.kr
- Publication Type:Original Article
- Keywords:
HMG-CoA reductase inhibitor;
PPARgamma agonist;
Pancreatic stellate cells;
Synergism
- MeSH:
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
- From:Gut and Liver
2012;6(2):262-269
- CountryRepublic of Korea
- Language:English
-
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.
