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(Circulation Research. 2009;104:219.)
© 2009 American Heart Association, Inc.

Integrative Physiology

Gene Transfer of Redox Factor-1 Inhibits Neointimal Formation

Involvement of Platelet-Derived Growth Factor-β Receptor Signaling via the Inhibition of the Reactive Oxygen Species–Mediated Syk Pathway

Hwan Myung Lee^*, Byeong Hwa Jeon^*, Kyung-Jong Won, Chang-Kwon Lee, Tae-Kyu Park, Wahn Soo Choi, Young Min Bae, Hyo Shin Kim, Sang Ki Lee, Seung Hwa Park, Kaikobad Irani, Bokyung Kim

From the Institute of Medical Sciences (H.M.L., K.-J.W., C.-K.L., T.-K.P., W.S.C., Y.M.B., S.H.P., B.K.), School of Medicine, Konkuk University, Danwol-dong, Chungju, South Korea; Infection Signaling Network Research Center (B.H.J., H.S.K., S.K.L.), Department of Physiology, Chungnam National University, South Korea; and Cardiovascular Institute (K.I.), University of Pittsburgh Medical Center, Pa.

Correspondence to Bokyung Kim, Department of Physiology, Institute of Medical Sciences, School of Medicine, Konkuk University, Danwol-dong 322, Chungju 380-701, South Korea. E-mail bkkim2{at}kku.ac.kr

The role of apurinic/apyrimidinic endonuclease-1/redox factor-1 (Ref-1) in vascular smooth muscle cells has yet to be clearly elucidated. Therefore, we attempted to determine the roles of Ref-1 in the migration induced by platelet-derived growth factor (PDGF)-BB and in its signaling in rat aortic smooth muscle cells (RASMCs). Cellular migration, superoxide (O₂^–·) production, Rac-1 activity, and neointima formation were determined in cells transfected with adenoviruses encoding for Ref-1 (AdRef-1) and small interference RNA of Ref-1. Overexpression of Ref-1 induced by treatment with RASMCs coupled with AdRef-1 inhibited the migration induced by PDGF-BB. PDGF-BB also increased the phosphorylation of the PDGFβ receptor, spleen tyrosine kinase (Syk), mitogen-activated protein kinase, and heat shock protein 27, but these increases were significantly inhibited by AdRef-1 treatment. PDGF-BB increased O₂^–· production and Rac-1 activity, and these were diminished in cells transfected with AdRef-1. In contrast, RASMC migration, phosphorylation of Syk and O₂^–· production in response to PDGF-BB were increased by the knock down of Ref-1 with small interference RNA. The phosphorylation of PDGFβ receptor in response to PDGF-BB was inhibited completely by the Syk inhibitor and was partly attenuated by a NADPH oxidase inhibitor. PDGF-BB increased the sprout outgrowth of the aortic ring ex vivo, which was inhibited in the AdRef-1–infected RASMCs as compared with the controls. Balloon injury–induced neointimal formation was significantly attenuated by the gene transfer of AdRef-1. These results indicate that Ref-1 inhibits the PDGF-mediated migration signal via the inhibition of reactive oxygen species–mediated Syk activity in RASMCs.

Key Words: apurinic/apyrimidinic endonuclease-1/redox factor-1 • vascular smooth muscle cells • migration reactive oxygen species • spleen tyrosine kinase

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