Abstract MP154: Deletion of the Duffy Antigen Receptor for Chemokines (DARC) Confers Protection Against Abdominal Aortic Aneurysm (AAA) Formation

Abstract

Introduction: Abdominal aortic aneurysms (AAA) are characterized by inflammation and matrix metalloproteinase (MMP)-mediated degradation of extra cellular matrix proteins leading to aortic dilation and potentially rupture. Inflammatory chemokines that promote AAA are modulated by binding to the Duffy antigen receptor for chemokines (DARC), a non-signaling receptor expressed primarily on erythrocytes. Interestingly, African Americans exhibit reduced frequency of AAA, and the majority of African descendent individuals do not express DARC on their erythrocytes. Here, we tested the hypothesis that DARC gene deletion protects against the development of AAA. Methods: The induction of AAA was performed using both angiotensin II (AngII) infusion and calcium chloride (CaCl 2 ) application models. Eight week old LDLR knockout (KO, control) and LDLR KO/DARC KO mice were infused with AngII via osmotic mini-pumps for four weeks. For the CaCl 2 application model, twelve week old DARC KO and WT control mice underwent laparotomy and 0.5 mol/L CaCl 2 was applied to the infrarenal aorta. Aortic dilation and AAA formation was assessed using ultrasound, mice were then euthanized and tissues were harvested for analysis. Results: The aortic diameter of LDLR KO/DARC KO mice was significantly lower relative to control mice after AngII infusion (P=0.02). There was no difference in the pressor response to AngII between groups. Furthermore, IL-6 levels were significantly reduced in the aortas of LDLR KO/DARC KO mice compared to control mice (P=0.001). Expression of MCP-1, which has strong affinity for DARC, tended to be higher in aortas from LDLR KO/DARC KO mice compared to control (P=0.063). In contrast, plasma IL-6 levels were similar in both LDLR KO/DARC KO and control mice, while MCP-1 tended to be lower in the plasma of LDLR KO/DARC KO (P=0.07). DARC KO mice likewise exhibited a trend toward reduced aortic dilation in the CaCl 2 application model compared to controls (P=0.09). Conclusions: DARC KO mice are protected against AAA formation, perhaps through differential regulation of aortic chemokine trafficking. Understanding the mechanisms by which loss of DARC confers protection from AAA formation may be relevant to ethnic differences in susceptibility to AAA.