title: PPARγ activation induces acute PAI-1 gene expression in the liver but not in adipose tissues of diabetic model mice.
abstract: Insulin resistance in patients with type II diabetes has recently been treated with thiazolidinediones, a class of peroxisome proliferator-activated receptor γ (PPARγ) agonists. However, these compounds are possibly associated with a significant increase in the risk of cardiovascular events. We examined the effect of the PPARγ agonist rosiglitazone on the expression of plasminogen activator inhibitor-1 (PAI-1) that is the primary inhibitor of fibrinolysis in the liver of diabetic mice and cultured mouse and human hepatocytes. Concentrations of plasma PAI-1 and levels of its mRNA expression in the liver were significantly elevated in accordance with hepatic PPARγ1 and PPARγ2 mRNA accumulation in genetically diabetic db/db mice. An intraperitoneal injection of rosiglitazone significantly increased plasma PAI-1 concentrations in parallel with hepatic, but not with adipose mRNA levels in db/db mice, and did not affect these parameters in wild-type mice. Rosiglitazone as well as the PPARα agonist bezafibrate significantly induced PAI-1 mRNA expression in cultured mouse hepatocytes. Furthermore, both rosiglitazone and pioglitazone significantly induced, whereas bezafibrate did not affect PAI-1 mRNA expression in the human liver carcinoma cell line HepG2. The transient induction of PAI-1 gene expression mediated by PPARγ in the fatty liver might be involved in the increased risk of cardiovascular events associated with thiazolidinediones in diabetic patients through decreasing fibrinolytic activity.
authors.affiliation: Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan. k-ooishi@aist.go.jp
authors.forename: Katsutaka
authors.initials: K
authors.lastname: Oishi
authors.forename: Tatsunosuke
authors.initials: T
authors.lastname: Tomita
authors.forename: Nanako
authors.initials: N
authors.lastname: Itoh
authors.forename: Naoki
authors.initials: N
authors.lastname: Ohkura
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D002318:Cardiovascular Diseases / Q000139:chemically induced; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology; D015533:Transcriptional Activation
chemical_list: D007004:Hypoglycemic Agents; D047495:PPAR gamma; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D045162:Thiazolidinediones; D000077154:Rosiglitazone