Early stimulation and late inhibition of peroxisome proliferator-activated receptor γ (PPARγ) gene expression by transforming growth factor β in human aortic smooth muscle cells:: role of early growth-response factor-1 (Egr-1), activator protein 1 (AP1) and Smads

Transforming growth factor beta (TGFbeta) and peroxisome proliferator-activated receptor gamma (PPARgamma) play major roles in the development of vascular diseases. It has been documented that PPARgamma activation inhibits the TGFbeta signal pathway in vascular smooth muscle cells (VSMC). Here we examined whether TGFbeta can regulate PPARgamma expression. Northern blot analyses revealed that both TGFbeta1 and 2 exert a biphasic effect (early stimulation and late repression) on PPARgamma gene expression in VSMC. TGFbeta rapidly and transiently induced early growth-response factor-1 (Egr-1) expression through the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1 (MEK1)/ERK-mediated pathway. Inhibition of MEK1/ ERK by PD98059 not only abrogated the induction of Egr-1 but also abolished the rapid and transient induction of PPARgamma by TGFbeta. Furthermore, overexpression of NAB2, a repressor of Egr-1 activation, also blocked the induction of PPARgamma by TGFbeta in VSMC, suggesting that Egr-1 mediates the rapid and transient induction of PPARgamma by TGFbeta. With regard to the TGFbeta repression of PPARgamma expression, activator protein 1 (AP1) and Smad3/4 dramatically inhibited the PPARgamma promoter activity in transient-transfection studies. In contrast, adenovirus-mediated overexpression of a dominant-negative form of c-Jun partially rescued the TGFbeta-induced PPARgamma repression in VSMC. Taken together, our data demonstrate that Egr-1, AP1 and Smad are part components of the TGFbeta signal transduction pathway that regulates PPARgamma expression.