The effects of combined treatment with an HMG-CoA reductase inhibitor and PPARγ agonist on the activation of rat pancreatic stellate cells

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Abstract

Background/Aims: Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) and peroxisome proliferator-activated receptor gamma (PPAR?) ligands can modulate cellular differentiation, proliferation, and apoptosis through various pathways. It has been shown that HMG-CoA reductase inhibitors and PPAR? 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 cellcycle progression. Methods: Primary cultures of rat PaSCs were exposed to simvastatin and troglitazone. Proliferation was quantifi ed 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.

Original languageEnglish
Pages (from-to)262-269
Number of pages8
JournalGut and Liver
Volume6
Issue number2
DOIs
Publication statusPublished - 2012 Apr 1

Fingerprint

troglitazone
Pancreatic Stellate Cells
Peroxisome Proliferator-Activated Receptors
Simvastatin
Platelet-Derived Growth Factor
Coenzyme A
Extracellular Signal-Regulated MAP Kinases
Oxidoreductases
Cell Proliferation
Cell Cycle Resting Phase
Cell Cycle
Cell Cycle Proteins
PPAR gamma
G1 Phase
Smooth Muscle
Actins
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Drug Combinations
Bromodeoxyuridine
Cell Survival

Keywords

  • HMG-CoA reductase inhibitor
  • Pancreatic stellate cells
  • PPARγ agonist
  • Synergism

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

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title = "The effects of combined treatment with an HMG-CoA reductase inhibitor and PPARγ agonist on the activation of rat pancreatic stellate cells",
abstract = "Background/Aims: Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) and peroxisome proliferator-activated receptor gamma (PPAR?) ligands can modulate cellular differentiation, proliferation, and apoptosis through various pathways. It has been shown that HMG-CoA reductase inhibitors and PPAR? 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 cellcycle progression. Methods: Primary cultures of rat PaSCs were exposed to simvastatin and troglitazone. Proliferation was quantifi ed 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.",
keywords = "HMG-CoA reductase inhibitor, Pancreatic stellate cells, PPARγ agonist, Synergism",
author = "Beomjae Lee and Lee, {Hong Sik} and Kim, {Chang Duck} and Jung, {Sung Woo} and Seo, {Yeon Seok} and Kim, {Yong Sik} and Jeen, {Yoon Tae} and Hoon-Jai Chun and Soon-Ho Um and Lee, {Sang Woo} and Choi, {Jai Hyun} and Ryu, {Ho Sang}",
year = "2012",
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doi = "10.5009/gnl.2012.6.2.262",
language = "English",
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pages = "262--269",
journal = "Gut and Liver",
issn = "1976-2283",
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T1 - The effects of combined treatment with an HMG-CoA reductase inhibitor and PPARγ agonist on the activation of rat pancreatic stellate cells

AU - Lee, Beomjae

AU - Lee, Hong Sik

AU - Kim, Chang Duck

AU - Jung, Sung Woo

AU - Seo, Yeon Seok

AU - Kim, Yong Sik

AU - Jeen, Yoon Tae

AU - Chun, Hoon-Jai

AU - Um, Soon-Ho

AU - Lee, Sang Woo

AU - Choi, Jai Hyun

AU - Ryu, Ho Sang

PY - 2012/4/1

Y1 - 2012/4/1

N2 - Background/Aims: Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) and peroxisome proliferator-activated receptor gamma (PPAR?) ligands can modulate cellular differentiation, proliferation, and apoptosis through various pathways. It has been shown that HMG-CoA reductase inhibitors and PPAR? 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 cellcycle progression. Methods: Primary cultures of rat PaSCs were exposed to simvastatin and troglitazone. Proliferation was quantifi ed 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.

AB - Background/Aims: Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) and peroxisome proliferator-activated receptor gamma (PPAR?) ligands can modulate cellular differentiation, proliferation, and apoptosis through various pathways. It has been shown that HMG-CoA reductase inhibitors and PPAR? 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 cellcycle progression. Methods: Primary cultures of rat PaSCs were exposed to simvastatin and troglitazone. Proliferation was quantifi ed 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.

KW - HMG-CoA reductase inhibitor

KW - Pancreatic stellate cells

KW - PPARγ agonist

KW - Synergism

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