The orphan nuclear receptor Nur77 suppresses endothelial cell activation through induction of IkappaBalpha expression.

Endothelial inflammation plays a critical role in the development and progression of cardiovascular disease, albeit the mechanisms need to be fully elucidated. Nur77 is highly expressed in vascular endothelial cells (ECs) and plays a role in the regulation of cell proliferation and angiogenesis; its role in vascular inflammation, however, remains unknown. Treatment of human umbilical vein ECs (HUVECs) with tumor necrosis factor (TNF)-alpha substantially increased the transcription and protein expression of Nur77 in a dose and time-dependent manner, as determined by Northern blot and Western blot analysis. Adenovirus mediated overexpression of Nur77 markedly increased the intracellular levels of I kappa B alpha by approximately 4-fold, whereas overexpression of dominant negative Nur77 (DN-Nur77), which lacks its transactivation domain, had no effect on I kappa B alpha expression, suggesting that Nur77 is an important transcriptional factor in controlling I kappa B alpha expression in ECs. Furthermore, overexpression of Nur77 significantly increased I kappa B alpha promoter activity via directly binding to a Nur77 response element in the I kappa B alpha promoter. Importantly, overexpression of Nur77, but not DN-Nur77, protected ECs against the TNF-alpha- and interleukin-1 beta-induced endothelial activation, as characterized by attenuation in the nuclear factor kappa B activation, expression of adhesion molecules ICAM-1 and VCAM-1, and monocytic adherence to ECs. These results indicate that Nur77 negatively regulates the TNF-alpha- and interleukin-1 beta-induced vascular EC activation by transcriptionally upregulation of I kappa B alpha expression. (Circ Res. 2009; 104: 742-749.)