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Originally published online as doi:10.2353/ajpath.2007.060838 on April 13, 2007

Published online before print April 13, 2007
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(American Journal of Pathology. 2007;170:2159-2170.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060838

Pigment Epithelium-Derived Factor Inhibits Neointimal Hyperplasia after Vascular Injury by Blocking NADPH Oxidase-Mediated Reactive Oxygen Species Generation

Kazuo Nakamura, Sho-ichi Yamagishi, Takanori Matsui, Takafumi Yoshida, Katsuhiko Takenaka, Yuko Jinnouchi, Yumiko Yoshida, Shin-ichiro Ueda, Hisashi Adachi and Tsutomu Imaizumi

From the Department of Medicine, Kurume University School of Medicine, Kurume, Japan

Pigment epithelium-derived factor (PEDF) inhibits cytokine-induced endothelial cell activation through its antioxidative properties. However, the effect of PEDF on restenosis remains to be elucidated. Because the pathophysiological feature of restenosis is characterized by increased superoxide formation and accumulation of smooth muscle cells (SMCs), PEDF may inhibit this process via suppression of reactive oxygen species generation. We investigated here whether PEDF could prevent neointimal formation after balloon injury. PEDF levels were decreased in balloon-injured arteries. Adenoviral vector encoding human PEDF (Ad-PEDF) prevented neointimal formation. Expression and superoxide generation of the membrane components of NADPH oxidase, p22phox and gp91phox, in the neointima were also suppressed by Ad-PEDF. Ad-PEDF reduced G1 cyclin (cyclin D1 and E) expression and increased p27, a cyclin-dependent kinase inhibitor. In vitro, PEDF inhibited platelet-derived growth factor-BB-induced SMC proliferation and migration by blocking reactive oxygen species generation through suppression of NADPH oxidase activity via down-regulation of p22PHOX and gp91PHOX. PEDF down-regulated G1 cyclins and up-regulated p27 levels in platelet-derived growth factor-BB-exposed SMCs as well. These results demonstrate that PEDF could inhibit neointimal formation via suppression of NADPH oxidase-mediated reactive oxygen species generation. Our present study suggests that substitution of PEDF may be a novel therapeutic strategy for restenosis after balloon angioplasty.






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Copyright © 2007 by the American Society for Investigative Pathology.