Abstract 19554: N-myc Downstream Regulated Gene-1 Regulates Endothelial Inflammation and Thrombotic Function
Introduction: N-myc downstream-regulated gene 1 (NDRG-1) is a member of NDRG family that plays essential roles in cell differentiation, proliferation, and stress responses. The expression of NDRG1 in vascular endothelial cells (ECs) is regulated by pathological stimuli, such as inflammatory cytokines and hyperhomocysteinemia. The role of NDRG1 in endothelial biology, however, remains poorly understood.
Hypothesis: Endothelial NDRG1 is essential for the development of inflammatory vascular diseases such as atherothrombosis.
Methods: The expression of NDRG1 in cytokine-stimulated ECs and in inflamed human aortic tissues was determined by using quantitative PCR (qPCR), western blot, and immunohistochemistry. In addition, we performed loss-of-function studies using NDRG1 specific small interference RNA (siRNA) to investigate the role of NDRG1 in endothelial activation and inflammation.
Results: Our results demonstrate that the expression of NDRG1 is markedly increased in both cytokine-stimulated ECs and in inflamed human aortic tissues. Furthermore, we found that knockdown of NDRG1 substantially attenuates both IL-1β and TNF-α-induced expression of cytokines/chemokines and adhesion molecules in ECs. Intriguingly, inhibition of NDRG1 also significantly attenuates the expression of procoagulant molecules, such as plasminogen activator inhibitor type 1 (PAI-1) and tissue factor (TF), and increases the expression of thrombomodulin and tissue-type plasminogen activator (t-PA), thus exerting potent anti-thrombotic effects in ECs. Mechanistically, we show that NDRG1 interacts with orphan nuclear receptor Nur77 and inhibition of NDRG1 expression increases transcriptional activity of Nur77, which leads to a subsequent inhibition of NF-κB activation in ECs. Moreover, in NDRG1 knockdown cells, both cytokine-induced c-Jun phosphorylation and AP-1 transcriptional activation are substantially inhibited.
Conclusions: Our results for the first time identify NDRG1 as a critical mediator implicated in endothelial inflammation and prothrombotic function, and suggest that inhibition of NDRG1 may represent a novel therapeutic strategy for inflammatory vascular diseases, such as atherosclerosis and thrombosis.
Author Disclosures: G. Zhang: None. Q. Qin: None. Z. Guo: None. B. Yi: None. L. Yin: None. Y. Yin: None. J. Chen: None. F. Cheng: None. Y. Wang: None. L. Han: None. S. Huang: None. Z. Xu: None. J. Sun: None.
- © 2016 by American Heart Association, Inc.