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

Park, J.B.; Kim, B.K.; Kwon, Y.W.; Muller, D.N.; Lee, H.C.; Youn, S.W.; Choi, Y.E.; Lee, S.W.; Yang, H.M.; Cho, H.J.; Park, K.W.; Kim, H.S.

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., Kim, B.K., Kwon, Y.W., Muller, D.N., Lee, H.C., Youn, S.W., Choi, Y.E., Lee, S.W., Yang, H.M., Cho, H.J., 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
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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