Korean J Nephrol.  2004 Jul;23(4):567-576.

Mechanisms Involved in the Inhibitory Effects of Mycophenolic Acid on the PDGF-induced Proliferation of Vascular Smooth Muscle Cells

• Park J
• Ha H
• Kim MS
• Huh KH
• Kim YS

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.

Keyword

Mycophenolic acid; Vascular smooth muscle cells; Platelet-derived growth factor (PDGF); Cell proliferation

MeSH Terms

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
Mitogen-Activated Protein Kinases
Mycophenolic Acid
NADPH Oxidase
RNA, Messenger
Reactive Oxygen Species
Thymidine
p38 Mitogen-Activated Protein Kinases