Mechanisms Involved in the Inhibitory Effects of Mycophenolic Acid on the PDGF-induced Proliferation of Vascular Smooth Muscle Cells.
- Author:
Jehyun PARK
1
;
Hunjoo HA
;
Myoung Soo KIM
;
Kyu Ha HUH
;
Yu Seun KIM
Author Information
1. The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, Korea. yukim@yumc.yonsei.ac.kr
- Publication Type:Original Article
- Keywords:
Mycophenolic acid;
Vascular smooth muscle cells;
Platelet-derived growth factor (PDGF);
Cell proliferation
- MeSH:
Allografts;
Animals;
Atherosclerosis;
Blotting, Western;
Cell Proliferation;
Humans;
Mitogen-Activated Protein Kinases;
Muscle, Smooth, Vascular*;
Mycophenolic Acid*;
NADPH Oxidase;
p38 Mitogen-Activated Protein Kinases;
Phosphorylation;
Rats;
Reactive Oxygen Species;
RNA, Messenger;
Thymidine;
Up-Regulation
- From:Korean Journal of Nephrology
2004;23(4):567-576
- CountryRepublic of Korea
- Language:Korean
-
Abstract:
BACKGROUND: Vascular smooth muscle cell (VSMC) proliferation plays an important role in the development and progression of chronic allograft vasculopathy as in atherosclerosis. We already reported that mycophenolic acid (MPA) inhibited VSMC proliferation, cellular reactive oxygen species (ROS) and mitogen-activated protein kinases (MAPK) in human VSMCs. In this study, we examined further molecular mechanisms involved in the anti-proliferative effect of MPA in rat VSMCs. METHODS: Primary rat VSMCs were stimulated with PDGF-BB 10 ng/mL in the presence or absence of MPA and various kinds of cell signaling inhibitors. Cell proliferation was assessed by [H3]- thymidine incorporation, NAD(P)H oxidase subunits mRNA expression by RT-PCR, dichlorofluorescein- sensitive cellular ROS by FACS, and the activation of PDGF receptor-beta (Tyr 751), rac1, and MAPK by Western blot analysis. RESULTS: PDGF increased cell proliferation and cellular ROS, activation of PDGF receptor-beta (Tyr 751), rac1, expression of p22phox and MOX1 mRNA, ERK 1/2, and p38 MAPK, compared to control. MPA inhibited up-regulation of rac1 phosphorylation, p22phox and MOX1 mRNA expression, cellular ROS, and phosphorylation of ERK 1/2 and p38 MAPK. However, MPA did not affect PDGF receptor-beta (Tyr 751) activation. Wortmannin, diphenyleniodonium (DPI), trolox, and NAC, each inhibited PDGF- induced ERK 1/2 and p38 MAPK activation. PD98059 and p38 MAPK inhibitor also inhibited PDGF-induced cell proliferation. CONCLUSION: These results suggest that MPA inhibits PDGF-induced VSMC proliferation through inhibiting NAD(P)H oxidase-dependent cellular ROS leading to ERK 1/2 and p38 MAPK activation.
