title: Peroxisome proliferator-activated receptor-gamma agonists suppress tissue factor overexpression in rat balloon injury model with paclitaxel infusion.
abstract: The role and underlying mechanisms of rosiglitazone, a peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonist, on myocardial infarction are poorly understood. We investigated the effects of this PPAR-γ agonist on the expression of tissue factor (TF), a primary molecule for thrombosis, and elucidated its underlying mechanisms. The PPAR-γ agonist inhibited TF expression in response to TNF-α 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-γ 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-γ 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-γ agonist in all cell types. This PPAR-γ 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-γ 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-γ 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.
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Jun-Bean
authors.initials: JB
authors.lastname: Park
authors.forename: Baek-Kyung
authors.initials: BK
authors.lastname: Kim
authors.forename: Yoo-Wook
authors.initials: YW
authors.lastname: Kwon
authors.forename: Dominik N
authors.initials: DN
authors.lastname: Muller
authors.forename: Hyun-Chae
authors.initials: HC
authors.lastname: Lee
authors.forename: Seock-Won
authors.initials: SW
authors.lastname: Youn
authors.forename: Young-Eun
authors.initials: YE
authors.lastname: Choi
authors.forename: Sae-Won
authors.initials: SW
authors.lastname: Lee
authors.forename: Han-Mo
authors.initials: HM
authors.lastname: Yang
authors.forename: Hyun-Jai
authors.initials: HJ
authors.lastname: Cho
authors.forename: Kyung Woo
authors.initials: KW
authors.lastname: Park
authors.forename: Hyo-Soo
authors.initials: HS
authors.lastname: Kim
mesh_terms: D000818:Animals; D002404:Catheterization; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007261:Infusions, Intra-Arterial; D008074:Lipoproteins / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists*; D017239:Paclitaxel / Q000008:administration & dosage*; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D020123:Sirolimus / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology*; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism*; D014469:Umbilical Arteries / Q000473:pathology
chemical_list: D008074:Lipoproteins; D047495:PPAR gamma; D012333:RNA, Messenger; D045162:Thiazolidinediones; C051928:lipoprotein-associated coagulation inhibitor; D000077154:Rosiglitazone; D013925:Thromboplastin; D020928:Mitogen-Activated Protein Kinases; D017239:Paclitaxel; D020123:Sirolimus