title: Paclitaxel induces thrombomodulin downregulation in human aortic endothelial cells.
abstract: Patients with paclitaxel-eluting stents are at risk of developing stent thrombosis upon premature discontinuation of dual antiplatelet therapy. In this study, we set out to clarify whether paclitaxel can modulate thrombomodulin expression in human aortic endothelial cells. Human aortic endothelial cells were stimulated with paclitaxel. Methoxyphenyl tetrazolium inner salt cell viability assay, Western blot analysis, real-time polymerase chain reaction, and immunohistochemical assay were performed. In human aortic endothelial cells, paclitaxel (10(-5) to 10(-9) mol/L) treatment for 13 hours caused significant cytotoxicity at drug concentrations greater than 10(-7) mol/L. Paclitaxel (10(-5) to 10(-9) mol/L) treatment for 5 hours downregulated thrombomodulin expression dose-dependently, persisting even at 13 hours. Cotreatment with thrombin and paclitaxel did not alter the effect of paclitaxel on thrombomodulin downregulation. Paclitaxel caused a 0.63-fold decrease in thrombomodulin messenger RNA expression, and thrombin cotreatment did not alter this decrease. In vivo studies confirmed that paclitaxel (10 mg/kg) caused endothelial thrombomodulin downregulation in mice. In summary, paclitaxel downregulates thrombomodulin expression regardless of thrombin stimulation, which is an important factor for patients receiving paclitaxel-eluting stents. Therefore, further designs of drug-eluting stents should consider the influence of the eluted drugs on endothelial thrombogenicity.
authors.affiliation: Institute of Biotechnology (Drs. H. Huang and Wang), National Tsing-Hua University, Hsinchu 30013, Republic of China.
authors.forename: Huang-Joe
authors.initials: HJ
authors.lastname: Wang
authors.forename: Te-Ling
authors.initials: TL
authors.lastname: Lu
authors.forename: Haimei
authors.initials: H
authors.lastname: Huang
authors.forename: Huey-Chun
authors.initials: HC
authors.lastname: Huang
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D017239:Paclitaxel / Q000494:pharmacology* / Q000633:toxicity; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013917:Thrombin / Q000378:metabolism; D018180:Thrombomodulin / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
chemical_list: D012333:RNA, Messenger; D018180:Thrombomodulin; D013917:Thrombin; D017239:Paclitaxel