Impact of thiazolidinedione therapy on atherogenesis.

Thiazolidinediones (TZDs), which are synthetic ligands for peroxisome proliferator activated receptor g (PPARg) activation, have been introduced in clinical medicine to improve insulin resistance and glycemic control in patients with type 2 diabetes. The metabolic effects of TZDs are mediated by receptor-dependent activation of the PPARg-retinoid X receptor (RXR) complex and subsequent transcriptional activation of target genes. The PPARg1 isoform is also expressed in endothelial cells, vascular smooth muscle cells, and monocytes/macrophages in the vasculature. TZDs have been shown to have anti-atherosclerotic effects on these cells in vitro, which appear to be partially independent of the PPARg-RXR-mediated transcriptional effects. Direct anti-atherosclerotic effects of TZDs include increased nitric oxide bioavailability, decreased leukocyte/endothelial cell interaction, reduced vascular smooth muscle cell migration and proliferation, and cholesterol efflux from macrophages. So far, there are no data on the effects of TZDs on cardiovascular events, but studies using surrogate markers of vascular disease provide preliminary evidence that TZDs delay progression of atherosclerosis in different patient groups. TZDs interfere with key processes in atherogenesis and may, therefore, offer additional opportunities to improve cardiovascular risk beyond treatment of glycemic control in patients with type 2 diabetes.