on November 29, 2004
Published online before print November 29, 2004, doi: 10.1161/01.ATV.0000151619.54108.a5
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Submitted on October 3, 2003
Accepted on November 10, 2004
Adenovirus-Mediated Intraarterial Delivery of PTEN Inhibits Neointimal Hyperplasia
Jianhua Huang ;
From the Department of Medicine (J.H., X.-L.N., A.M.P., B.H.A., C.D.K.), Division of Cardiology and Department of Pharmacology (C.D.K.) and Cancer Biology, Duke University Medical Center, Durham, NC.
* To whom correspondence should be addressed. E-mail: cdkontos{at}duke.edu.
Objective--Phosphoinositide (PI) 3-kinase promotes vascular smooth muscle cell (VSMC) responses necessary for neointimal hyperplasia. We recently demonstrated that the inositol 3-phosphatase PTEN is expressed in VSMCs and that its overexpression inhibits these cellular responses. The purpose of this study was to determine the effects of adenovirus-mediated overexpression of PTEN on neointimal hyperplasia in vivo in the rat carotid injury model.
Methods and Results--Rat carotid arteries were balloon-injured and treated with a recombinant control adenovirus (AdEV) (n=6), an adenovirus encoding wild-type PTEN (AdPTEN) (n=8), or phosphate-buffered saline (sham) (n=5). Injured vessels demonstrated PTEN overexpression by Western blotting and immunohistochemistry after AdPTEN treatment. Neointimal hyperplasia was assessed 2 weeks after balloon injury and adenovirus administration. Compared with controls, AdPTEN treatment significantly decreased neointimal area and percent stenosis. To investigate the mechanisms of action of AdPTEN, vessels were harvested 3 days after balloon injury and virus infection. AdPTEN significantly increased medial cell apoptosis while decreasing proliferation of the remaining viable cells.
Conclusions--PTEN overexpression potently inhibits neointimal hyperplasia through induction of apoptosis and inhibition of medial cell proliferation. These findings suggest that modulation of PTEN expression or activity may be a viable approach to treat neointimal hyperplasia.
Key words: apoptosis • PTEN • vascular biology • neointimal hyperplasia • phosphoinositide 3-kinase
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