Antiproliferative agents alter vascular plasminogen activator inhibitor-1 expression: A potential prothrombotic mechanism of drug-eluting stents

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

*Corresponding author for this work

Research output: Contribution to journalArticle

63 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)400-406
Number of pages7
JournalArteriosclerosis, thrombosis, and vascular biology
Volume27
Issue number2
DOIs
StatePublished - Feb 2007

Keywords

  • Antiproliferative
  • Endothelial cells
  • Gene expression
  • Plasminogen activator inhibitor 1
  • Rapamycin paclitaxel gene array

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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