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

Autor/innen

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

Journal

  • PLoS ONE

Quellenangabe

  • PLoS ONE 6 (11): e28327

Zusammenfassung

  • 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.


DOI

doi:10.1371/journal.pone.0028327