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Suppression of c-Cbl tyrosine phosphorylation inhibits neointimal formation in balloon-injured rat arteries
Tang Z.2; Wang Y.2; Fan Y.2; Zhu Y.2; Chien S.1; Wang N.2
2008-08-12
Source PublicationCirculation
ISSN00097322 15244539
Volume118Issue:7Pages:764-772
AbstractBackground - c-Cbl, a ubiquitously expressed protooncogene, is tyrosine phosphorylated in response to a variety of stimuli, including growth factors such as platelet-derived growth factor (PDGF), and consequently activates signaling proteins such as phosphatidylinositol-3 kinase (PI3K) and Akt. In the present study, we examined the role of c-Cbl tyrosine phosphorylation in vascular injury. Methods and Results - Western blotting showed that the tyrosine phosphorylation of c-Cbl was increased in balloon-injured rat carotid arteries and in cultured smooth muscle cells on stimulation by PDGF-BB, followed by the activations of Akt and the mammalian target of rapamycin. Adenovirus-mediated overexpression of a c-Cbl mutant that ablates the major tyrosine phosphorylation sites attenuated the Akt and the mammalian target of rapamycin activation and decreased the proliferation and migration of smooth muscle cells in response to PDGF-BB or fibroblast growth factor. These effects could be reversed by constitutively active PI3K or Akt, suggesting that c-Cbl phosphorylation promotes the PDGF-BB-induced proliferation and migration of smooth muscle cells through the PI3K/Akt pathways. In addition, overexpression of c-Cbl-m increased the ubiquitination of the PDGF and fibroblast growth factor receptors. Importantly, in balloon-injured rat carotid arteries, local delivery of c-Cbl-m reduced the phosphorylation of Akt and the mammalian target of rapamycin, inhibited the migration and proliferation of smooth muscle cells, and prevented neointimal hyperplasia. Conclusions - Our results demonstrate a novel role of c-Cbl in vascular remodeling after injury and suggest that modulation of c-Cbl tyrosine phosphorylation may be a therapeutic approach to treat vascular neointimal hyperplasia such as restenosis after angioplasty. © 2008 American Heart Association, Inc.
KeywordAngioplasty Gene therapy Restenosis Signal transduction Vessels
DOI10.1161/CIRCULATIONAHA.107.761932
URLView the original
Language英語
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Cited Times [WOS]:14   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionUniversity of Macau
Affiliation1.University of California, San Diego
2.Peking University
Recommended Citation
GB/T 7714
Tang Z.,Wang Y.,Fan Y.,et al. Suppression of c-Cbl tyrosine phosphorylation inhibits neointimal formation in balloon-injured rat arteries[J]. Circulation,2008,118(7):764-772.
APA Tang Z.,Wang Y.,Fan Y.,Zhu Y.,Chien S.,&Wang N..(2008).Suppression of c-Cbl tyrosine phosphorylation inhibits neointimal formation in balloon-injured rat arteries.Circulation,118(7),764-772.
MLA Tang Z.,et al."Suppression of c-Cbl tyrosine phosphorylation inhibits neointimal formation in balloon-injured rat arteries".Circulation 118.7(2008):764-772.
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