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(Circulation. 2008;118:764-772.)
© 2008 American Heart Association, Inc.

Vascular Medicine

Suppression of c-Cbl Tyrosine Phosphorylation Inhibits Neointimal Formation in Balloon-Injured Rat Arteries

Zhihui Tang, MD; Ying Wang, MD; Yanbo Fan, MD; Yi Zhu, MD; Shu Chien, MD, PhD; Nanping Wang, MD, PhD

From the Institute of Cardiovascular Science and Key Laboratory for Molecular Cardiovascular Sciences, Ministry of Education, Peking University, Beijing, China (Z.T., Y.W., Y.F., Y.Z., N.W.), and Departments of Bioengineering and Medicine, University of California San Diego, La Jolla (S.C.).

Correspondence to Nanping Wang, MD, PhD, Institute of Cardiovascular Science, Peking University Health Science Center, Beijing 100083, China (e-mail npwang{at}bjmu.edu.cn); or Shu Chien, MD, PhD, Department of Bioengineering, University of California San Diego, 9500 Gilman Dr, La Jolla, CA 92093–0412 (e-mail shuchien@ucsd.edu).

Received December 28, 2007; accepted June 10, 2008.

Background— 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.

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CLINICAL PERSPECTIVE

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Clinical Summaries
Circulation 2008 118: 697-698. [Extract] [Full Text]