Abstract 18851: RAGE/sRAGE Antagonism Unveils a Novel Therapeutic Target and Biomarker of Thoracic Aortic Aneurysm and Dissection

    loading  Checking for direct PDF access through Ovid

Abstract

Introduction: The Receptor for Advanced Glycation End Products (RAGE), when activated, induces irreversible vascular tissue injury and the release of soluble RAGE (sRAGE) in the circulation. We demonstrated that plasma sRAGE is increased in patients with a high incidence of thoracic aortic aneurysm and dissection (TAAD), such as patients with Bicuspid Aortic Valve disease (BAV) and Marfan syndrome (MFS). In these patients, plasma sRAGE correlates with the presence of a dysfunctional aortic structure (increased elastin fragmentation and matrix deposition) and with overexpression of RAGE in aneurysmal tissue.

We hypothesize that circulating sRAGE in TAAD is the result of aberrant RAGE activation in the aortic wall and that blocking RAGE could alter the progression of TAAD.

Methods: Our hypothesis was tested in two mouse models of TAAD: the AngII chronic infusion model and the hypomorphic, fibrillin 1 deficient mice (FBN1mgR/mgR) which resembles the most severe form of TAAD in MFS. Mice were treated with losartan or with a RAGE antagonist (RAP). Ascending aorta and blood were collected at day 28 of AngII infusion or at post natal day 90 in FBN1mgR/mgR. Aortic dilatation and degeneration were assessed by echocardiography and histology.

Results: RAGE antagonism inhibits aneurysm formation in AngII animals treated with RAP when compared to untreated (1.9± 0.03 vs 1.4± 0.04 mm p<0.001). RAP treatment significantly improves the survival and reduces aortic aneurysm development in FBN1mgR/mgR animals when compared to placebo (2 ± 0.02 vs 1.6 ± 0.004 mm, p=0.008). Histological analysis showed that RAP treatment reduces aortic fibrosis, media thickening and elastin fragmentation. Circulating sRAGE increases in both TAAD models in concomitance with vascular remodeling and aneurysm formation and decreases upon treatment with RAP or losartan.

Conclusions: RAGE antagonism counteracts the development of aortic aneurysm by inhibiting vascular remodeling in mice models of TAAD. Circulating sRAGE correlates with the presence of aortic dilatation and decreases upon treatments that inhibit aneurysmal formation. These results highlight the role of RAGE/sRAGE axis in aneurysmal disease and unveil novel potential therapeutic targets and circulating biomarkers of TAAD.

Related Topics

    loading  Loading Related Articles