Gene transfer of redox factor-1 inhibits neointimal formation: involvement of platelet-derived growth factor-beta receptor signaling via the inhibition of the reactive oxygen species-mediated Syk pathway.

Authors: Lee, HM  Jeon, BH  Won, KJ  Lee, CK  Park, TK  Choi, WS  Bae, YM  Kim, HS  Lee, SK  Park, SH  Irani, K  Kim, B 
Citation: Lee HM, etal., Circ Res. 2009 Jan 30;104(2):219-27, 5p following 227. Epub 2008 Nov 26.
Pubmed: (View Article at PubMed) PMID:19038866
DOI: Full-text: DOI:10.1161/CIRCRESAHA.108.178699

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 (O(2)(-*)) 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 PDGFbeta 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 O(2)(-*) production and Rac-1 activity, and these were diminished in cells transfected with AdRef-1. In contrast, RASMC migration, phosphorylation of Syk and O(2)(-*) production in response to PDGF-BB were increased by the knock down of Ref-1 with small interference RNA. The phosphorylation of PDGFbeta 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.

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CRRD Object Information
CRRD ID: 2315669
Created: 2010-01-07
Species: All species
Last Modified: 2010-01-07
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.