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Cardiovascular Research 2003 60(3):673-683; doi:10.1016/j.cardiores.2003.09.018
© 2003 by European Society of Cardiology
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Copyright © 2003, European Society of Cardiology

Differential cyclin E expression in human in-stent stenosis smooth muscle cells identifies targets for selective anti-restenosis therapy

Michael O'Sullivana, Stephen D Scotta, Nicola McCarthya, Nicola Figga, Leonard M Shapirob, Peter Kirkpatrickc and Martin R Bennett*,a

aDivision of Cardiovascular Medicine, Cambridge University, Box 110, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK
bCardiac Unit, Papworth Hospital, Cambridge, UK
cDepartment of Neurosurgery, Addenbrooke's Hospital, UK

*Corresponding author. Tel.: +44-1223-331504; fax: +44-1223-331505. Email address: mrb{at}mole.bio.cam.ac.uk

Objective: Cell cycle inhibitors are promising agents to prevent or treat human coronary in-stent stenosis (ISS). However, their lack of specificity for ISS vascular smooth muscle cells (VSMCs) may inhibit medial VSMC proliferation and suppress vessel healing. Methods: To identify inhibitor targets that differentially regulate proliferation of ISS vs. medial VSMCs, we examined cell cycle regulation in human VSMCs derived from (A) normal media, (B) ISS sites and (C) primary atherosclerotic plaques (P-VSMCs) using time-lapse videomicroscopy, flow cytometry, immunoblotting and immunohistochemistry. Results: ISS-VSMC proliferation was intermediate between P-VSMCs and medial VSMCs. Compared with medial cells, P-VSMCs expressed increased p16 and p21, reduced p27, reduced cyclins D1 and E, and reduced pRb phosphorylation. In contrast, ISS-VSMCs expressed high levels of cyclins E and A with pRb hyperphosphorylation, both in vitro and in vivo, associated with increased and chronic cell proliferation in vivo. Roscovitine, a selective CDK2 inhibitor, inhibited VSMC proliferation by both pRb-dependent and independent pathways and more potently in ISS-VSMCs than medial VSMCs. Conclusions: Human ISS-VSMCs have marked differences in the stable expression of multiple cell cycle regulators, suggesting that ISS-VSMCs derive from P-VSMCs driven to proliferate through cyclin E overexpression. The critical role for cyclin E–CDK2 enables the identification of the first agent that selectively inhibits ISS-VSMC proliferation.

KEYWORDS Restenosis; Smooth muscle; Atherosclerosis

time for primary review 21 days


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