Mycophenolic Acid Inhibits Cell Proliferation and Extracellular Matrix Synthesis in Rat Vascular Smooth Muscle Cells Through Direct and Indirect Inhibition of Cellular Reactive Oxygen Species

Jehyun Park, Hye Kyung Chang, Hunjoo Ha, Myoung Soo Kim, Hyung Joon Ahn, Yu Seun Kim

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Background: Vascular smooth muscle cell (VSMC) proliferation and extracellular matrix (ECM) accumulation play important roles in the development and progression of chronic allograft vasculopathy. Although mycophenolic acid (MPA) inhibits activation of mesenchymal cells through cellular reactive oxygen species (ROS), the exact mechanisms involved in theses processes have not been clearly understood. This study explored the molecular mechanisms whereby MPA inhibits cellular ROS-mediated VSMC proliferation and ECM synthesis. Materials and methods: Primary rat VSMCs were stimulated with platelet-derived growth factor (PDGF)-BB in the presence or absence of MPA 0.1-10 μmol/L or guanosine 100 μmol/L. Cell proliferation was assessed by methylthiazoletetrazolium and proliferating cell nuclear antigen expression, fibronectin secretion, and rac1 membrane translocation by Western blot analysis, total collagen synthesis by [3H]-proline incorporation, dichlorofluorescein-sensitive cellular ROS by confocal microscopy, and hydrogen peroxide (H2O2) concentration by iodometric analysis. Results: MPA inhibited PDGF-induced VSMC proliferation, ECM synthesis, and cellular ROS, and these inhibitions were partially reversed by exogenous guanosine. MPA at dose inhibiting PDGF-induced VSMC activation inhibited rac1 membrane translocation, and this inhibition was fully recovered by exogenous guanosine. Additionally, MPA rapidly reduced H2O2 concentration in vitro. Conclusions: The present study suggests that MPA inhibits PDGF-induced VSMC proliferation and ECM synthesis through inhibiting rac1-dependent cellular ROS and directly scavenging ROS. Both direct and indirect inhibition of cellular ROS would be the key mechanisms involved in the inhibitory effect of MPA in VSMCs.

Original languageEnglish
Pages (from-to)17-23
Number of pages7
JournalJournal of Surgical Research
Volume150
Issue number1
DOIs
Publication statusPublished - 2008 Nov 1

Fingerprint

Mycophenolic Acid
Vascular Smooth Muscle
Smooth Muscle Myocytes
Extracellular Matrix
Reactive Oxygen Species
Cell Proliferation
Guanosine
Platelet-Derived Growth Factor
Membranes
Proliferating Cell Nuclear Antigen
Fibronectins
Proline
Confocal Microscopy
Hydrogen Peroxide
Allografts
Collagen
Western Blotting

All Science Journal Classification (ASJC) codes

  • Surgery

Cite this

@article{2c01f9f8dbf84b3690ca674a28ab673e,
title = "Mycophenolic Acid Inhibits Cell Proliferation and Extracellular Matrix Synthesis in Rat Vascular Smooth Muscle Cells Through Direct and Indirect Inhibition of Cellular Reactive Oxygen Species",
abstract = "Background: Vascular smooth muscle cell (VSMC) proliferation and extracellular matrix (ECM) accumulation play important roles in the development and progression of chronic allograft vasculopathy. Although mycophenolic acid (MPA) inhibits activation of mesenchymal cells through cellular reactive oxygen species (ROS), the exact mechanisms involved in theses processes have not been clearly understood. This study explored the molecular mechanisms whereby MPA inhibits cellular ROS-mediated VSMC proliferation and ECM synthesis. Materials and methods: Primary rat VSMCs were stimulated with platelet-derived growth factor (PDGF)-BB in the presence or absence of MPA 0.1-10 μmol/L or guanosine 100 μmol/L. Cell proliferation was assessed by methylthiazoletetrazolium and proliferating cell nuclear antigen expression, fibronectin secretion, and rac1 membrane translocation by Western blot analysis, total collagen synthesis by [3H]-proline incorporation, dichlorofluorescein-sensitive cellular ROS by confocal microscopy, and hydrogen peroxide (H2O2) concentration by iodometric analysis. Results: MPA inhibited PDGF-induced VSMC proliferation, ECM synthesis, and cellular ROS, and these inhibitions were partially reversed by exogenous guanosine. MPA at dose inhibiting PDGF-induced VSMC activation inhibited rac1 membrane translocation, and this inhibition was fully recovered by exogenous guanosine. Additionally, MPA rapidly reduced H2O2 concentration in vitro. Conclusions: The present study suggests that MPA inhibits PDGF-induced VSMC proliferation and ECM synthesis through inhibiting rac1-dependent cellular ROS and directly scavenging ROS. Both direct and indirect inhibition of cellular ROS would be the key mechanisms involved in the inhibitory effect of MPA in VSMCs.",
author = "Jehyun Park and Chang, {Hye Kyung} and Hunjoo Ha and Kim, {Myoung Soo} and Ahn, {Hyung Joon} and Kim, {Yu Seun}",
year = "2008",
month = "11",
day = "1",
doi = "10.1016/j.jss.2007.09.011",
language = "English",
volume = "150",
pages = "17--23",
journal = "Journal of Surgical Research",
issn = "0022-4804",
publisher = "Academic Press Inc.",
number = "1",

}

Mycophenolic Acid Inhibits Cell Proliferation and Extracellular Matrix Synthesis in Rat Vascular Smooth Muscle Cells Through Direct and Indirect Inhibition of Cellular Reactive Oxygen Species. / Park, Jehyun; Chang, Hye Kyung; Ha, Hunjoo; Kim, Myoung Soo; Ahn, Hyung Joon; Kim, Yu Seun.

In: Journal of Surgical Research, Vol. 150, No. 1, 01.11.2008, p. 17-23.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Mycophenolic Acid Inhibits Cell Proliferation and Extracellular Matrix Synthesis in Rat Vascular Smooth Muscle Cells Through Direct and Indirect Inhibition of Cellular Reactive Oxygen Species

AU - Park, Jehyun

AU - Chang, Hye Kyung

AU - Ha, Hunjoo

AU - Kim, Myoung Soo

AU - Ahn, Hyung Joon

AU - Kim, Yu Seun

PY - 2008/11/1

Y1 - 2008/11/1

N2 - Background: Vascular smooth muscle cell (VSMC) proliferation and extracellular matrix (ECM) accumulation play important roles in the development and progression of chronic allograft vasculopathy. Although mycophenolic acid (MPA) inhibits activation of mesenchymal cells through cellular reactive oxygen species (ROS), the exact mechanisms involved in theses processes have not been clearly understood. This study explored the molecular mechanisms whereby MPA inhibits cellular ROS-mediated VSMC proliferation and ECM synthesis. Materials and methods: Primary rat VSMCs were stimulated with platelet-derived growth factor (PDGF)-BB in the presence or absence of MPA 0.1-10 μmol/L or guanosine 100 μmol/L. Cell proliferation was assessed by methylthiazoletetrazolium and proliferating cell nuclear antigen expression, fibronectin secretion, and rac1 membrane translocation by Western blot analysis, total collagen synthesis by [3H]-proline incorporation, dichlorofluorescein-sensitive cellular ROS by confocal microscopy, and hydrogen peroxide (H2O2) concentration by iodometric analysis. Results: MPA inhibited PDGF-induced VSMC proliferation, ECM synthesis, and cellular ROS, and these inhibitions were partially reversed by exogenous guanosine. MPA at dose inhibiting PDGF-induced VSMC activation inhibited rac1 membrane translocation, and this inhibition was fully recovered by exogenous guanosine. Additionally, MPA rapidly reduced H2O2 concentration in vitro. Conclusions: The present study suggests that MPA inhibits PDGF-induced VSMC proliferation and ECM synthesis through inhibiting rac1-dependent cellular ROS and directly scavenging ROS. Both direct and indirect inhibition of cellular ROS would be the key mechanisms involved in the inhibitory effect of MPA in VSMCs.

AB - Background: Vascular smooth muscle cell (VSMC) proliferation and extracellular matrix (ECM) accumulation play important roles in the development and progression of chronic allograft vasculopathy. Although mycophenolic acid (MPA) inhibits activation of mesenchymal cells through cellular reactive oxygen species (ROS), the exact mechanisms involved in theses processes have not been clearly understood. This study explored the molecular mechanisms whereby MPA inhibits cellular ROS-mediated VSMC proliferation and ECM synthesis. Materials and methods: Primary rat VSMCs were stimulated with platelet-derived growth factor (PDGF)-BB in the presence or absence of MPA 0.1-10 μmol/L or guanosine 100 μmol/L. Cell proliferation was assessed by methylthiazoletetrazolium and proliferating cell nuclear antigen expression, fibronectin secretion, and rac1 membrane translocation by Western blot analysis, total collagen synthesis by [3H]-proline incorporation, dichlorofluorescein-sensitive cellular ROS by confocal microscopy, and hydrogen peroxide (H2O2) concentration by iodometric analysis. Results: MPA inhibited PDGF-induced VSMC proliferation, ECM synthesis, and cellular ROS, and these inhibitions were partially reversed by exogenous guanosine. MPA at dose inhibiting PDGF-induced VSMC activation inhibited rac1 membrane translocation, and this inhibition was fully recovered by exogenous guanosine. Additionally, MPA rapidly reduced H2O2 concentration in vitro. Conclusions: The present study suggests that MPA inhibits PDGF-induced VSMC proliferation and ECM synthesis through inhibiting rac1-dependent cellular ROS and directly scavenging ROS. Both direct and indirect inhibition of cellular ROS would be the key mechanisms involved in the inhibitory effect of MPA in VSMCs.

UR - http://www.scopus.com/inward/record.url?scp=53449100970&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=53449100970&partnerID=8YFLogxK

U2 - 10.1016/j.jss.2007.09.011

DO - 10.1016/j.jss.2007.09.011

M3 - Article

C2 - 17950325

AN - SCOPUS:53449100970

VL - 150

SP - 17

EP - 23

JO - Journal of Surgical Research

JF - Journal of Surgical Research

SN - 0022-4804

IS - 1

ER -