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Cited 5 time in webofscience Cited 6 time in scopus
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The Effects of Combined Treatment with an HMG-CoA Reductase Inhibitor and PPAR gamma Agonist on the Activation of Rat Pancreatic Stellate Cells

Authors
Lee, Beom JaeLee, Hong SikKim, Chang DuckJung, Sung WooSeo, Yeon SeokKim, Yong SikJeen, Yoon TaeChun, Hoon JaiUm, Soon HoLee, Sang WooChoi, Jai HyunRyu, Ho Sang
Issue Date
Apr-2012
Publisher
EDITORIAL OFFICE GUT & LIVER
Keywords
HMG-CoA reductase inhibitor; PPAR gamma agonist; Pancreatic stellate cells; Synergism
Citation
GUT AND LIVER, v.6, no.2, pp.262 - 269
Indexed
SCIE
SCOPUS
KCI
OTHER
Journal Title
GUT AND LIVER
Volume
6
Number
2
Start Page
262
End Page
269
URI
https://scholarworks.korea.ac.kr/kumedicine/handle/2020.sw.kumedicine/12274
DOI
10.5009/gnl.2012.6.2.262
ISSN
1976-2283
Abstract
Background/Aims: Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) and peroxisome proliferator-activated receptor gamma (PPAR gamma) ligands can modulate cellular differentiation, proliferation, and apoptosis through various pathways. It has been shown that HMG-CoA reductase inhibitors and PPAR gamma 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. (Gut Liver 2012;6:262-269)
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Seo, Yeon Seok
Anam Hospital (Department of Gastroenterology and Hepatology, Anam Hospital)
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