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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

Authors :
Park, Jehyun
Chang, Hye Kyung
Ha, Hunjoo
Kim, Myoung Soo
Ahn, Hyung Joon
Kim, Yu Seun
Source :
Journal of Surgical Research. Nov2008, Vol. 150 Issue 1, p17-23. 7p.
Publication Year :
2008

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. [Copyright &y& Elsevier]

Details

Language :
English
ISSN :
00224804
Volume :
150
Issue :
1
Database :
Academic Search Index
Journal :
Journal of Surgical Research
Publication Type :
Academic Journal
Accession number :
34748513
Full Text :
https://doi.org/10.1016/j.jss.2007.09.011