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

Authors: Park, JB  Kim, BK  Kwon, YW  Muller, DN  Lee, HC  Youn, SW  Choi, YE  Lee, SW  Yang, HM  Cho, HJ  Park, KW  Kim, HS 
Citation: Park JB, etal., PLoS One. 2011;6(11):e28327. doi: 10.1371/journal.pone.0028327. Epub 2011 Nov 29.
Pubmed: (View Article at PubMed) PMID:22140576
DOI: Full-text: DOI:10.1371/journal.pone.0028327

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.

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CRRD Object Information
CRRD ID: 11341672
Created: 2016-06-30
Species: All species
Last Modified: 2016-06-30
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.