Abstract 11622: Resolution of Inflammation via Rvd1/fpr2 Signaling in Abdominal Aortic Aneurysms

Abstract

Introduction: Resolvin D1 (RvD1) is derived from a ω-3 polyunsaturated fatty acid and is involved in the resolution phase of inflammation during abdominal aortic aneurysm (AAA) formation. Hypothesis: The aim of this study was to decipher the protective role of RvD1 via formyl peptide receptor 2 (FPR2) receptor signaling in attenuating AAA formation. Methods: C57BL/6 (WT) and FPR2 -/- mice (8-12 week old) underwent treatment with topical elastase or heat-inactivated elastase (control). Separate groups of mice were administered RvD1 (100ng/kg) or saline i.p. daily from day(d)1 to d13 and aortic diameter was measured by video micrometry on d14. mRNA quantification of FPR2 expression in aortic tissue was performed by RT-PCR on d7, 14 and 21. Human aortic tissue from AAA patients and controls (organ transplant donors) were analyzed for quantification of FPR2 expression. Data is presented as mean ± SEM and statistical analysis was performed by using Mann-Whitney test for phenotype or Wilcoxon Signed Rank Test for gene expression data. Results: Elastase-treated WT mice had significantly increased aortic diameter compared to controls (127±8% vs. 1± 0.6%; p<0.0001). Importantly, elastase-treated FPR2 -/- had a significant increase in aortic diameter compared to elastase-treated WT mice (165±16% vs. 127± 8%; p=0.03). RvD1 treatment attenuated AAA formation in WT mice, but not FPR2 -/- mice, on d14 (56± 10% vs.121± 8%; p<0.0001). Immunohistology documented decreased elastin and smooth muscle cell α-actin expression, as well as increased neutrophil and macrophage infiltration in FPR2 -/- mice compared to WT mice, after respective treatments with RvD1. Elastase-treated WT mice had significantly increased FPR2 receptor mRNA expression compared to respective controls on d7, d14, and d21. Human AAA tissue demonstrated significantly decreased FPR2 mRNA expression compared to controls (p=0.02). Conclusions: This data identifies the role of FPR2 in dysregulation of inflammation-resolution during AAA pathogenesis. Immunomodulation of FPR2 signaling by exogenous RvD1 identifies a novel mechanism in resolution of aortic inflammation and vascular remodeling during AAA pathogenesis.