Published Online
on July 6, 2004

A more recent version of this article appeared on July 20, 2004

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Submitted on December 18, 2003
Revised on March 25, 2004
Accepted on April 2, 2004

Celecoxib, a Cyclooxygenase-2 Inhibitor, Reduces Neointimal Hyperplasia Through Inhibition of Akt Signaling

Han-Mo Yang MD, Hyo-Soo Kim MD^*, Kyung-Woo Park MD, Hyun-Jeong You BA, Soo-In Jeon BA, Seock-Won Youn MS, Sung-Hwan Kim MD, Byung-Hee Oh MD, Myoung-Mook Lee MD, Young-Bae Park MD, and Kenneth Walsh PhD

From the Cardiovascular Laboratory, Clinical Research Institute, Seoul National University Hospital (H.M.Y., H.S.K., K.W.P., H.J.Y., S.I.J., S.W.Y., S.H.K., B.H.O., M.M.L., Y.B.P.), and the Department of Internal Medicine, Seoul National University College of Medicine (H.M.Y., H.S.K., K.W.P., S.H.K., B.H.O., M.M.L., Y.B.P.), Seoul, Korea; and the Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Mass (K.W.).

^* To whom correspondence should be addressed. E-mail: hyosoo{at}snu.ac.kr.

Background--Celecoxib has been shown to have antitumor effects that may be mediated through the cyclooxygenase-independent inhibition of Akt signaling. Here, we examined the effects of celecoxib on neointimal formation after balloon injury and its mechanism of action.

Methods and Results--In vitro experiments were performed to evaluate the effects of celecoxib on the Akt/GSK signaling axis and the viability of rat vascular smooth muscle cells (VSMCs). In vivo experiments examined the effects of celecoxib, aspirin, and vehicle on neointimal growth after denudation injury to rat carotid arteries. In vitro, celecoxib suppressed the phosphorylation of Akt and GSK in cultured VSMCs, leading to a reduction in viable cell number, which was reversed by transduction of constitutively active Akt. Such a reduction in cell number was mediated by inhibition of proliferation and induction of apoptosis. In vivo, celecoxib reduced injury-induced phosphorylation of Akt and GSK, reduced VSMC proliferation, and increased caspase-3 activation and VSMC apoptosis at 3 days after injury, whereas aspirin had no effect. At 2 weeks after injury, celecoxib reduced intima-to-media ratio, whereas aspirin had no effect. Adenovirus-mediated delivery of dominant negative Akt was as effective as celecoxib at inhibiting neointimal formation. Conversely, gene delivery of constitutively active Akt significantly reversed the inhibition of intimal hyperplasia by celecoxib, providing causal evidence that the modulation of Akt signaling by celecoxib is a physiologically relevant mechanism.

Conclusions--Celecoxib is a potential inhibitor of neointimal formation by blocking injury-induced Akt activation. These findings suggest a potential use for celecoxib in the prevention of restenosis after angioplasty.

Key words: Akt • cyclooxygenase inhibitors • restenosis • apoptosis • muscle, smooth

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