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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 
 JOURNAL OF SURGICAL RESEARCH, Vol.150(1) : 17-23, 2008 
Journal Title
Issue Date
Animals ; Antibiotics, Antineoplastic/pharmacology* ; Aorta/cytology ; Becaplermin ; Cell Membrane/metabolism ; Cell Proliferation/drug effects* ; Cells, Cultured ; Extracellular Matrix/metabolism* ; Guanosine/biosynthesis ; Hydrogen Peroxide/metabolism ; Mycophenolic Acid/pharmacology* ; Myocytes, Smooth Muscle/drug effects* ; Platelet-Derived Growth Factor/pharmacology ; Proto-Oncogene Proteins c-sis ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism* ; rac1 GTP-Binding Protein/antagonists & inhibitors
vascular smooth muscle cells ; extracellular matrix ; mycophenolic acid ; reactive oxygen species ; rac1
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 micromol/L or guanosine 100 micromol/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 [(3)H]-proline incorporation, dichlorofluorescein-sensitive cellular ROS by confocal microscopy, and hydrogen peroxide (H(2)O(2)) 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 H(2)O(2) 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.
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1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Myoung Soo(김명수) ORCID logo https://orcid.org/0000-0002-8975-8381
Kim, Yu Seun(김유선) ORCID logo https://orcid.org/0000-0002-5105-1567
Chang, Hye Kyung(장혜경)
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