Increasing evidence indicates an important role of PPARgamma activation in modulating the development and progression of atherosclerosis, however, the mechanisms involved in these effects are not well understood since the PPARgamma-regulated genes in vascular smooth muscle cells (VSMC) are poorly defined. Here we reported that PPARgamma ligands, GW7845, ciglitazone and troglitazone had the effect of inhibiting osteoprotegerin (OPG) expression in human aortic smooth muscle cells (HASMC). The effect of GW7845 and ciglitazone on OPG expression was completely abolished by GW9662, a PPARgamma antagonist. Overexpression of PPARgamma in HASMC by the infection of a PPARgamma adenovirus dramatically decreased OPG expression. In addition, PPARgamma activation inhibited OPG promoter activity. Taken together, our data suggest that OPG expression is a novel PPARgamma target gene in VSMC and downregulation of OPG expression by PPARgamma activation provides a new insight into the understanding of the role of PPARgamma in atherosclerosis and hypertension. (C) 2002 Elsevier Science (USA). All rights reserved.