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Cardiovascular Research Advance Access first published online on July 3, 2008
This version [Corrected Proof] published online on July 24, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn188
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Rho GTPase, Rac1, regulates Skp2 levels, vascular smooth muscle cell proliferation, and intima formation in vitro and in vivo

Mark Bond1,{dagger},*, Wu Yih-Jer2,3,{dagger}, Graciela B. Sala-Newby1 and Andrew C. Newby1

1 Bristol Heart Institute, University of Bristol, Level 7, Bristol Royal Infirmary, Bristol BS2 8HW, UK
2 Cardiovascular Division, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan
3 Institute of Traditional Medicine, National Yang-Ming University, Taipei, Taiwan

* Corresponding author. Tel: +44 117 9283586; fax: +44 117 9283581. E-mail address: mark.bond{at}bristol.ac.uk

Aims: Vascular smooth muscle cell (VSMC) proliferation contributes to intima formation after angioplasty or venous by-pass grafting, and during atherosclerosis. VSMC proliferation requires degradation of p27Kip1 promoted by S-phase kinase-associated protein-2 (Skp2), an F-box protein component of the Skp-Cullin-F-boxSkp2 ubiquitin-ligase. We investigated the role of Rac1 in the regulation of Skp2 in rat VSMC.

Methods and results: Rat carotid balloon injury increased Rac1 activity. Rho GTPase inhibition with Clostridium difficile Toxin B or specific Rac1 inhibition with adenovirus-mediated expression of dominant-negative Rac1 reduced Skp2 levels, and VSMC proliferation in vitro and intima formation in vivo following carotid balloon injury. Inhibition of Skp2 expression and proliferation by dominant-negative Rac1 was reversed by exogenous Skp2. Elevation of endogenous adenosine 3',5'-cyclic monophosphate (cAMP) with forskolin-inhibited Rac1 activity, reduced Skp2, increased p27Kip1 and inhibited VSMC proliferation, effects that were reversed by constitutively active Rac1. These effects were independent of Rac1 Cdc42/Rac interactive binding (CRIB)-domain effector proteins but associated with Rac1-dependent actin polymerization.

Conclusion: Rac1 activity regulates VSMC proliferation by controlling Skp2 levels. Activation of Rac1 induced by balloon injury in vivo increases Skp2 levels, which promotes VSMC proliferation and intima formation. Inhibition of this novel pathway underlies the negative effects of cAMP on VSMC proliferation.

KEYWORDS Skp2; Rac; Cell cycle; Neointima; Smooth muscle cell

Time for primary review: 28 days

{dagger} Both authors contributed equally.


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