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(Circulation Research. 2009;104:742.)
© 2009 American Heart Association, Inc.

Molecular Medicine

The Orphan Nuclear Receptor Nur77 Suppresses Endothelial Cell Activation Through Induction of IB Expression

Bei You, Yuan-Ying Jiang, Shaoping Chen, Guijun Yan, Jianxin Sun

From the Departments of Pharmacology (B.Y., Y.-Y.J., J.S.) and Medicine (S.C.), Second Military Medical University, Shanghai, People’s Republic of China; Reproductive Medicine Center (G.Y.), The Affiliated Drum Tower Hospital of Nanjing University, Nanjing, People’s Republic of China; and the Department of Cell Biology and Molecular Medicine (B.Y., J.S.), University of Medicine and Dentistry of New Jersey–New Jersey Medical School, Newark.

Correspondence to Jianxin Sun, PhD, Department of Cell Biology and Molecular Medicine, UMDNJ-New Jersey Medical School, 185 S Orange Ave, MSB G-653, Newark, NJ 07103. E-mail sunj1{at}umdnj.edu

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)- 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 IB by approximately 4-fold, whereas overexpression of dominant negative Nur77 (DN-Nur77), which lacks its transactivation domain, had no effect on IB expression, suggesting that Nur77 is an important transcriptional factor in controlling IB expression in ECs. Furthermore, overexpression of Nur77 significantly increased IB promoter activity via directly binding to a Nur77 response element in the IB promoter. Importantly, overexpression of Nur77, but not DN-Nur77, protected ECs against the TNF-– and interleukin-1β–induced endothelial activation, as characterized by attenuation in the nuclear factor 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-– and interleukin-1β–induced vascular EC activation by transcriptionally upregulation of IB expression.

Key Words: Nur77 • endothelial cells • nuclear factor B • IB • atherosclerosis

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Nur77: Orphaned at Birth but Adopted by the Nuclear Factor B Signaling Pathway

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