Abstract 9691: Group X Secretory Phospholipase A 2 in Neutrophils Plays a Pathogenic Role in Abdominal Aortic Aneurysms in Mice

Abstract

Group X secretory phospholipase A 2 (sPLA 2 -X) is expressed in neutrophils and plays a role in the pathogenesis of neutrophil-mediated tissue inflammation and injury. Neutrophils have a critical role in development of abdominal aortic aneurysms. This study tested the hypothesis that sPLA 2 -X in neutrophils may contribute to the pathogenesis of abdominal aortic aneurysms using sPLA 2 -X knockout (sPLA 2 -X -/- ) mice. Methods and Results: Abdominal aortic aneurysms were created by application of CaCl 2 (0.5M) to the external surface of the aorta. As a result, a half of sPLA 2 -X +/+ mice had abdominal aortic aneurysm (> 50% increase in aortic diameter from pretreatment) 6 weeks after CaCl 2 treatment, while none of sPLA 2 -X -/- mice had it. The aortas of sPLA 2 -X -/- mice had smaller diameters (% increase from pretreatment, 26.0 ± 3.7 vs. 42.4 ± 7.0, respectively, p < 0.01), a reduced grade of elastin degradation and lower activities of elastase and gelatinase after CaCl 2 treatment compared with sPLA 2 -X +/+ mice. In sPLA 2 -X +/+ mice, immunofluorescence microscopic images showed that the immunoreactivity of sPLA 2 -X was detected only in neutrophils within aortic walls 3 days, 1, 2 and 6 weeks after CaCl 2 treatment, while the immunoreactivity was not detected in macrophages, mast cells or other cells in the aortic walls. Also, sPLA 2 -X immunoreactivity was colocalized in neutrophils expressing MMP-9. Neutrophils isolated from sPLA 2 -X -/- mice had lower activities of elastase, gelatinase and MMP-9 in response to PMA or fMLP compared with sPLA 2 -X +/+ mice. The attenuated release of proteases from sPLA 2 -X -/- neutrophils was reversed by the exogenous addition of mouse sPLA 2 -X protein. The aortic diameters and elastin degradation grades were significantly reduced in the lethally irradiated sPLA 2 -X +/+ mice reconstituted with sPLA 2 -X -/- bone marrow compared to irradiated sPLA 2 -X +/+ mice reconstituted with sPLA 2 -X +/+ bone marrow. The adoptive transfer of sPLA 2 -X +/+ neutrophils reversed aortic diameters and elastin degradation grade in the lethally irradiated sPLA 2 -X +/+ mice reconstituted with sPLA 2 -X -/- bone marrow to a similar extent seen in sPLA 2 -X +/+ mice. Conclusions: sPLA 2 -X in neutrophils plays a critical role in the pathogenesis of abdominal aortic aneurysms.