Review of the pleiotropic effects of peroxisome proliferator-activated receptor gamma agonists on platelet function.

The primary target receptor for thiazolidinediones (TZDs) or peroxisome proliferator-activated receptor gamma (PPARgamma) agonists is a transcription factor in the nucleus of adipocytes and other metabolically active cells, where they improve insulin sensitivity and glucose utilization. TZDs are also able to modify gene expression in macrophages, smooth muscle cells, and endothelial cells. Although PPARgamma is considered to be a nuclear receptor, enucleate platelets also highly express this receptor. The aim of this review is to present the current understanding of a direct or indirect effect of TZDs on platelet function. By means of a comprehensive literature search (January 1990-June 2006), publications were obtained that contained specific information about in vitro and in vivo effects of TZDs on platelet function. The effects were studied for different risk biochemical markers, i.e., proteins found to be elevated in the state of procoagulant inflammation and endothelial dysfunction. Improvement of platelet function was reported for all TZDs-troglitazone, pioglitazone, and rosiglitazone. The described effects included reduction of platelet aggregation, suppression of thrombin-induced protein kinase C-alpha and -beta activation, decrease in plasma P-selectin and platelet P-selectin expression, increase in nitric oxide production, inhibition of the Rho/Rho kinase pathway, and inhibition of tissue factor- and platelet-activating factor-induced morphological changes in macrophages. These findings appeared in parallel with reduction of the plasma concentrations of pro-inflammatory risk markers. TZDs seem to have a direct pleiotropic positive influence on platelet function and coagulation and may be helpful in treating the prothrombotic state observed in patients with type 2 diabetes and metabolic syndrome.