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.
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