Paclitaxel Potentiates Inflammatory Cytokine-induced Prothrombotic Molecules in Endothelial Cells

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Abstract

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.

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