Transforming growth factor β (TGFβ) and peroxisome proliferator-activated receptor γ (PPARγ) play major roles in the development of vascular diseases. It has been documented that PPARγ activation inhibits the TGFβ signal pathway in vascular smooth muscle cells (VSMC). Here we examined whether TGFβ can regulate PPARγ expression. Northern blot analyses revealed that both TGFβ1 and 2 exert a biphasic effect (early stimulation and late repression) on PPARγ gene expression in VSMC. TGFβ 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 PPARγ by TGFβ. Furthermore, overexpression of NAB2, a repressor of Egr-1 activation, also blocked the induction of PPARγ by TGFβ in VSMC, suggesting that Egr-1 mediates the rapid and transient induction of PPARγ by TGFβ. With regard to the TGFβ repression of PPARγ expression, activator protein 1 (AP1) and Smad3/4 dramatically inhibited the PPARγ promoter activity in transient-transfection studies. In contrast, adenovirus-mediated overexpression of a dominant-negative form of c-Jun partially rescued the TGFβ-induced PPARγ repression in VSMC. Taken together, our data demonstrate that Egr-1, AP1 and Smad are part components of the TGFβ signal transduction pathway that regulates PPARγ expression.
Abbreviations used: AngII, angiotensin II; AP1, activator protein 1; bFGF, basic fibroblast growth factor; BMP2, bone morphogenic protein 2; CTGF, connective-tissue growth factor; Egr-1, early growth-response factor-1; ERK, extracellular signal-regulated kinase; GADPH, glyceraldehyde-3-phosphate dehydrogenase; GFP, green fluorescent protein; HASMC, human aortic smooth muscle cells; IL-1β, interleukin 1β; MAPK, mitogen-activated protein kinase; MEK1, MAPK/ERK kinase 1; NAB2, nerve-growth-factor-induced A-binding proteins 2; PDGF, platelet-derived growth factor; pERK, phospho-ERK; PPARγ, peroxisome proliferator-activated receptor γ; TGFβ, transforming growth factor β; TNFα, tumour necrosis factor α; VSMC, vascular smooth muscle cells.