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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:400.)
© 2007 American Heart Association, Inc.

Thrombosis

Antiproliferative Agents Alter Vascular Plasminogen Activator Inhibitor-1 Expression

A Potential Prothrombotic Mechanism of Drug-Eluting Stents

James A.S. Muldowney, III; John R. Stringham; Shawn E. Levy; Linda A. Gleaves; Mesut Eren; Robert N. Piana; Douglas E. Vaughan

From the Division of Cardiovascular Medicine, Department of Medicine (J.A.S.M., J.R.S., L.A.G., M.E., R.N.P., D.E.V.), the Department of Molecular Physiology and Biophysics (S.E.L.), and the Department of Pharmacology (D.E.V.), Vanderbilt University Medical Center, Nashville, Tenn.

Correspondence to Douglas E. Vaughan, MD, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, 383 Preston Research Building, Nashville, Tennessee 37232-6300. E-mail doug.vaughan{at}vanderbilt.edu

Objectives— Drug eluting stents (DES) reduce the incidence of restenosis after coronary angioplasty. Enthusiasm has been tempered by a possible increased risk of in-stent thrombosis. We examined the effects of paclitaxel and rapamycin on the endothelial transcriptome to identify alterations in gene expression associated with thrombosis.

Methods and Results— Gene expression profiling was performed on human coronary artery endothelial cells treated with rapamycin or paclitaxel. Plasminogen activator inhibitor-1 (PAI-1) was the most consistently induced transcript in rapamycin-treated human coronary artery endothelial cells. RT-PCR and ELISA were performed to confirm positive findings. Transgenic mice engineered to express enhanced green fluorescent protein under control of the human PAI-1 promoter were also treated. Rapamycin and paclitaxel treated endothelial cells produced dose-dependent increases in PAI-1. There was a variable effect on endothelial tissue-type plasminogen activator (t-PA) expression. Enhanced expression of PAI-1 and enhanced green fluorescent protein were detected in coronary arteries, the aorta, and kidney of the mice.

Conclusion— Antiproliferative agents stimulate the expression of prothrombotic genes. PAI-1 expression may also play a role in the prevention of restenosis through an antimigratory mechanism. The effects of antiproliferatives on vascular gene expression deserve further scrutiny in view of the increasing utilization of drug-eluting stents.

To examine the prothrombotic effects of antiproliferative agents on endothelial gene expression, coronary endothelial cells were treated with paclitaxel or rapamycin. Transcriptional profiling was performed and confirmed by RT-PCR, ELISA, and a murine model. Rapamycin and paclitaxel induced increases in endothelial PAI-1 in the coronary arteries and aortas of mice.

Key Words: antiproliferative • plasminogen activator inhibitor 1 • rapamycin paclitaxel gene array • endothelial cells • gene expression

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Emerging Thrombotic Effects of Drug Eluting Stents

Ninian N. Lang and David E. Newby
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