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Peroxisome proliferator-activated receptor-gamma agonists suppress tissue factor overexpression in rat balloon injury model with Paclitaxel infusion

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Item Type:Article
Title:Peroxisome proliferator-activated receptor-gamma agonists suppress tissue factor overexpression in rat balloon injury model with Paclitaxel infusion
Creators Name:Park, J.B. and Kim, B.K. and Kwon, Y.W. and Muller, D.N. and Lee, H.C. and Youn, S.W. and Choi, Y.E. and Lee, S.W. and Yang, H.M. and Cho, H.J. and Park, K.W. and Kim, H.S.
Abstract:The role and underlying mechanisms of rosiglitazone, a peroxisome proliferator-activated receptor-gamma (PPAR-{gamma}) agonist, on myocardial infarction are poorly understood. We investigated the effects of this PPAR-{gamma} agonist on the expression of tissue factor (TF), a primary molecule for thrombosis, and elucidated its underlying mechanisms. The PPAR-{gamma} agonist inhibited TF expression in response to TNF-{alpha} in human umbilical vein endothelial cells, human monocytic leukemia cell line, and human umbilical arterial smooth muscle cells. The overexpression of TF was mediated by increased phosphorylation of mitogen-activated protein kinase (MAPK), which was blocked by the PPAR-{gamma} agonist. The effective MAPK differed depending on each cell type. Luciferase and ChIP assays showed that transcription factor, activator protein-1 (AP-1), was a pivotal target of the PPAR-{gamma} agonist to lower TF transcription. Intriguingly, two main drugs for drug-eluting stent, paclitaxel or rapamycin, significantly exaggerated thrombin-induced TF expression, which was also effectively blocked by the PPAR-{gamma} agonist in all cell types. This PPAR-{gamma} agonist did not impair TF pathway inhibitor (TFPI) in three cell types. In rat balloon injury model (Sprague-Dawley rats, n = 10/group) with continuous paclitaxel infusion, the PPAR-{gamma} agonist attenuated TF expression by 70±5% (n = 4; P<0.0001) in injured vasculature. Taken together, rosiglitazone reduced TF expression in three critical cell types involved in vascular thrombus formation via MAPK and AP-1 inhibitions. Also, this PPAR-{gamma} agonist reversed the paclitaxel-induced aggravation of TF expression, which suggests a possibility that the benefits might outweigh its risks in a group of patients with paclitaxel-eluting stent implanted.
Keywords:Animals, Rats
Source:PLoS ONE
ISSN:1932-6203
Publisher:Public Library of Science (U.S.A.)
Volume:6
Number:11
Page Range:e28327
Date:29 November 2011
Official Publication:https://doi.org/10.1371/journal.pone.0028327
PubMed:View item in PubMed

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