Abstract 695: Rage-mDia1 Mediates Vascular Remodeling in Angiotensin Ii Induced Thoracic Aortic Aneurysm

Abstract

Background: The Receptor for Advanced Glycation End Products (RAGE), when activated, induces irreversible vascular tissue injury by promoting pro-oxidative and pro-inflammatory signaling pathways. RAGE signal transduction requires the engagement of RAGE cytoplasmic domain with the formin Diaphanous 1 (mDia1) and results in the release of soluble RAGE in the circulation. We have previously demonstrated that the RAGE/sRAGE axis is involved in the development and progression of thoracic aortic aneurysm (TAA) in humans and mice. Elevated levels of sRAGE are found in aneurysmal patients and in mouse models of TAA. In addition, RAGE inhibition counteracts aortic dilatation and the release of sRAGE in the circulation. We hypothesize that RAGE induced vascular remodeling in TAA is mediated by mDia1. Methods: AngII infusion (1000 ng/Kg/min) was performed in C57BL6 male mice, fed with hypercolesterolaemic diet. Mice were treated for 4 weeks with losartan or with a RAGE antagonist (RAP). Ascending aortas of treated animals were harvested at day 28 post-infusion. Aortic dilatation and degeneration were assessed by echocardiography and histology. Immunofluorescence and Real Time PCR were performed to evaluate the expression of RAGE, mDia1, extracellular matrix proteins (ECM) and pro-inflammatory genes. Results: AngII infusion induces ascending aorta dilatation and medial thickening characterized by a substantial ECM deposition. RAGE and mDia1 expression is significantly increased in the aneurysmal aorta of mice chronically infused with AngII together with up-regulation of pro-inflammatory molecules (IL-6, MCP-1, IL1beta, TLR4, CCR2) and markers of extracellular matrix remodeling (Col1, Col3, MMP-2 and MMP12). Inhibition of RAGE dampens mDia1 expression and significantly reduces medial pro-inflammatory and pro-fibrotic signals while counteracting aneurysm formation. Conclusion: Formin mDia1 is involved in RAGE mediated TAA formation. Strategies that block RAGE-mDia1 interaction may unveil novel therapeutic approaches for the treatment of TAA.