PPAR gamma activation in human endothelial cells increases plasminogen activator inhibitor type-1 expression - PPAR gamma as a potential mediator in vascular disease

Plasminogen activator inhibitor type-1 (PAI-1) is a major physiological inh ibitor of fibrinolysis, with its plasma levels correlating with the risk fo r myocardial infarction and venous thrombosis. The regulation of PAI-1 tran scription by endothelial cells (ECs), a major source of PAI-1, remains inco mpletely understood. Adipocytes also produce PAI-1, suggesting possible com mon regulatory pathways between adipocytes and ECs. Peroxisomal proliferato r-activated receptor-gamma (PPAR)gamma is a ligand-activated transcription factor that regulates gene expression in response to Various mediators such as 15-deoxy-(Delta 12,14)- prostaglandin J(2) (15d-PGJ(2)) and oxidized li noleic acid (9- and 13-HODE). The present study tested the hypotheses that human ECs express PPAR gamma and that this transcriptional activator regula tes PAI-1 expression in this cell type. We found that human ECs contain bot h PPAR gamma mRNA and protein. Immunohistochemistry of human carotid arteri es also revealed the presence of PPAR gamma in ECs. Bovine ECs transfected with a PPAR response element (PPRE)-luciferase construct responded to stimu lation by the PPAR gamma agonist 15d-PGJ(2) in a concentration-dependent ma nner, suggesting a functional PPAR gamma in ECs. Treatment of human ECs wit h 15d-PGJ(2), 9(S)-HODE, or 13(S)-HODE augmented PAI-1 mRNA and protein exp ression, whereas multiple PPAR alpha activators did not change PAI-1 levels . Introduction of increasing amounts of a PPAR gamma expression construct i n human fibroblasts enhanced PAI-1 secretion from these cells in proportion to the amount of transfected DNA. Thus, ECs express functionally active PP AR gamma that regulates PAI-1 expression in ECs. Our results establish a ro le for PPAR gamma in the regulation of EC gene expression, with important i mplications for the clinical links between obesity and atherosclerosis.