Nuclear Receptor Nur77 Protects Against Abdominal Aortic Aneurysm by Ameliorating Inflammation Via Suppressing LOX‐1

Abstract

Background Abdominal aortic aneurysm (AAA) is a life‐threatening vascular disorder characterized by chronic inflammation of the aortic wall, which lacks effective pharmacotherapeutic remedies and has an extremely high mortality. Nuclear receptor NR4A1 (Nur77) functions in various chronic inflammatory diseases. However, the influence of Nur77 on AAA has remained unclear. Herein, we sought to determine the effects of Nur77 on the development of AAA. Methods and Results We observed that Nur77 expression decreased significantly in human and mice AAA lesions. Deletion of Nur77 accelerated the development of AAA in mice, as evidenced by increased AAA incidence, abdominal aortic diameters, elastin fragmentation, and collagen content. Consistent with genetic manipulation, pharmacological activation of Nur77 by celastrol showed beneficial effects against AAA. Microscopic and molecular analyses indicated that the detrimental effects of Nur77 deficiency were associated with aggravated macrophage infiltration in AAA lesions and increased pro‐inflammatory cytokines secretion and matrix metalloproteinase (MMP‐9) expression. Bioinformatics analyses further revealed that LOX‐1 was upregulated by Nur77 deficiency and consequently increased the expression of cytokines and MMP‐9. Moreover, rescue experiments verified that LOX‐1 notably aggravated inflammatory response, an effect that was blunted by Nur77. Conclusions This study firstly demonstrated a crucial role of Nur77 in the formation of AAA by targeting LOX‐1, which implicated Nur77 might be a potential therapeutic target for AAA.

Keywords

• abdominal
• angiotensin II
• aortic aneurysm
• inflammation
• macrophage
• nuclear receptor