To explore the molecular mechanisms of PPARgamma1 gene expression in vascular smooth muscle cells (VSMC), we hypothesized that early growth-response factor-1 (Egr-1) might be a transcriptional mediator of the growth factor- and cytokine-induced PPARgamma1 gene expression since a putative Egr-1 binding element was found in the human PPARgamma1 promoter. In this study, we document that overexpression of Egr-1 activates the human PPARgamma1 promoter in both VSMC and HepG2 cells. Using Northern blot analysis, we observed that growth factors and cytokines such as PDGF, bFGF, Ang II, TNFalpha, and IL-1beta induce Egr-1 expression prior to PPARgamma1 up-regulation in human VSMC. In addition, overexpression of a constitutively active form of Egr-1 by adenoviral gene transfer in VSMC dramatically induced PPARgamma1 gene expression by 6-8-fold, and overexpression of NAB2, a potent negative feedback regulator of Egr-1, abrogated the growth factor- and cytokine-induced PPARgamma1 expression in VSMC. Furthermore, we demonstrate with gel mobility shift and transient transfection assays that the putative Egr-1 element in the human PPARgamma1 promoter specifically binds Egr-1 protein and becomes trans-activated by Egr-1. Taken together, our data demonstrate for the first time that Egr-1 is necessary and sufficient to activate human PPARgamma1 gene expression in VSMC.