Troglitazone reduces plasminogen activator inhibitor-1 expression and secretion in cultured human adipocytes.

Abstract

Increased plasma plasminogen activator inhibitor-1 (PAI-1) concentrations are characteristic for subjects with insulin resistance and could contribute to the increased cardiovascular risk in this state. In this study, we investigated the effect of troglitazone, a ligand of the nuclear receptor peroxisome proliferator activated receptor-gamma, on PAI-1 expression and secretion in human adipocytes. We used two models: in vitro differentiated subcutaneous and omental adipocytes cultured under serum-free conditions and isolated subcutaneous and omental fat cells kept in suspension culture. Plasminogen activator inhibitor-1 protein was measured by ELISA, PAI-1 mRNA by a semiquantitative RT-PCR technique. Exposure of in vitro differentiated subcutaneous adipocytes from young normal-weight females to 1 microgram/ml troglitazone for 72 h caused a reduction of both PAI-1 secretion (by 29 +/- 5%; p < 0.01) and PAI-1 mRNA expression (by 26 +/- 3%; p < 0.05). In cultures from severely obese subjects, troglitazone induced a decrease of PAI-1 antigen secretion from newly differentiated omental adipocytes by 49 +/- 8% (p < 0.01) and from subcutaneous adipocytes by 30 +/- 7% (p < 0.05). Exposure of freshly isolated subcutaneous and omental adipocytes in suspension culture to troglitazone induced a similar reduction of PAI-1 concentration in the culture medium (by 35 +/- 11%, p < 0.05, and 33 +/- 8%, p < 0.05 compared with control, respectively). This study provides evidence that troglitazone reduces PAI-1 production in human adipocytes, probably at the transcriptional level. This observation could point to a new beneficial effect of troglitazone, particularly in obese subjects, which could be associated with a reduced cardiovascular risk.