Original ArticlePaclitaxel Potentiates Inflammatory Cytokine-induced Prothrombotic Molecules in Endothelial CellsWood, Steven C PhD*; Tang, Xing MD, PhD*; Tesfamariam, Belay PhD†Author Information From the *Office of Science and Engineering Laboratories, Center for Devices and Radiological Health; and †Division of Cardiovascular and Renal Products, Center for Drug Evaluation and Research, FDA, Silver Spring, MD. Received for publication June 8, 2009; December 7, 2009. The authors report no conflicts of interest. Reprints: Steven Wood, PhD, Office of Science and Engineering Laboratories, CDRH, FDA, Bldg 64, Rm 3026, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002 (e-mail: [email protected]). Journal of Cardiovascular Pharmacology: March 2010 - Volume 55 - Issue 3 - p 276-285 doi: 10.1097/FJC.0b013e3181d263f7 Buy Metrics Abstract To overcome the limitations of balloon expandible metal stent-induced neointimal smooth muscle cell proliferation, drug-coated stent devices have been developed. Drug eluting stents release high concentrations of antiproliferative agents, such as paclitaxel, to reduce neointimal hyperplasia. The proinflammatory cytokine, tumor necrosis factor-α (TNF-α), is known to cause severe endothelial dysfunction and accelerate atherosclerotic lesion progression. The interaction of TNF-α and paclitaxel on the release of prothrombotic molecules was examined in endothelial cells. Treatment of endothelial cells with paclitaxel had no direct effect on tissue factor (TF) expression, but TNF-α increased TF. Cotreatment of paclitaxel with TNF-α markedly augmented the release of TF. TNF-α induced release of plasminogen activator inhibitor but no synergism occurred with paclitaxel. Treatment of endothelial cells with paclitaxel and TNF-α reduced expression of thrombomodulin and protein C receptor. Tissue factor pathway inhibitor expression was reduced by prolonged treatment with either paclitaxel or TNF-α. The adhesion molecule, CD62 E, was induced by TNF-α; however, CD31, CD62 P, and CD106 were not affected by paclitaxel and TNF-α. Apoptosis was not observed with cotreatment of endothelial cells with paclitaxel and TNF-α. CD59-positive microparticles were released in response to TNF-α, but the release was not augmented by paclitaxel. Paclitaxel and TNF-α increased the nitrotyrosination of proteins. These findings indicate that paclitaxel enhances TNF-α-induced release of TF, and downregulated thrombomodulin, increased protein nitration, which may subsequently favor prothrombotic intimal surface. © 2010 Lippincott Williams & Wilkins, Inc.