RAGE deficiency ameliorates abdominal aortic aneurysm progression.

Abstract

Background: Abdominal aortic aneurysm (AAA) is a vascular disease characterized by inflammation and arterial wall degradation. The receptor for advanced glycation end products (RAGE) plays a pivotal role in regulating inflammatory pathways, but its specific contribution to AAA pathogenesis remains unclear.

Purpose: This study aimed to investigate the role of RAGE in AAA development by examining its expression in human and mice AAA tissues and exploring the effects of RAGE deficiency on aneurysm progression, macrophage polarization, and inflammatory responses.

Methods: RAGE expression was analyzed in human AAA samples and porcine pancreatic elastase (PPE) induced AAA mouse models using Western blotting, immunohistochemistry, and immunofluorescence. In vivo RAGE-deficient (RAGE^-/-) mice were generated to assess the impact of RAGE knockout on AAA progression. In vitro experiments utilized RAW264.7 transfected with RAGE-targeting siRNA to study macrophage polarization and NF-κB signaling.

Results: RAGE expression was elevated in AAA tissues, particularly in macrophages. RAGE^-/- mice exhibited reduced AAA incidence, mortality, and aortic dilation compared to wild-type mice. Histological analysis showed preserved elastic fibers and smooth muscle layers, along with decreased inflammatory cell infiltration and MMP2/MMP9 expression. RAGE deficiency inhibited M1-like macrophage polarization and pro-inflammatory cytokine secretion, mediated through suppression of the NF-κB pathway.

Conclusions: RAGE deficiency mitigates AAA progression by modulating macrophage polarization and reducing inflammation via the NF-κB pathway. These findings highlight RAGE as a potential therapeutic target for AAA treatment.