Abstract 9691: Group X Secretory Phospholipase A2 in Neutrophils Plays a Pathogenic Role in Abdominal Aortic Aneurysms in Mice
Group X secretory phospholipase A2 (sPLA2-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 sPLA2-X in neutrophils may contribute to the pathogenesis of abdominal aortic aneurysms using sPLA2-X knockout (sPLA2-X-/-) mice.
Methods and Results: Abdominal aortic aneurysms were created by application of CaCl2 (0.5M) to the external surface of the aorta. As a result, a half of sPLA2-X+/+ mice had abdominal aortic aneurysm (> 50% increase in aortic diameter from pretreatment) 6 weeks after CaCl2 treatment, while none of sPLA2-X-/- mice had it. The aortas of sPLA2-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 CaCl2 treatment compared with sPLA2-X+/+ mice. In sPLA2-X+/+mice, immunofluorescence microscopic images showed that the immunoreactivity of sPLA2-X was detected only in neutrophils within aortic walls 3 days, 1, 2 and 6 weeks after CaCl2 treatment, while the immunoreactivity was not detected in macrophages, mast cells or other cells in the aortic walls. Also, sPLA2-X immunoreactivity was colocalized in neutrophils expressing MMP-9. Neutrophils isolated from sPLA2-X-/- mice had lower activities of elastase, gelatinase and MMP-9 in response to PMA or fMLP compared with sPLA2-X+/+ mice. The attenuated release of proteases from sPLA2-X-/- neutrophils was reversed by the exogenous addition of mouse sPLA2-X protein. The aortic diameters and elastin degradation grades were significantly reduced in the lethally irradiated sPLA2-X+/+ mice reconstituted with sPLA2-X-/- bone marrow compared to irradiated sPLA2-X+/+ mice reconstituted with sPLA2-X+/+ bone marrow. The adoptive transfer of sPLA2-X+/+ neutrophils reversed aortic diameters and elastin degradation grade in the lethally irradiated sPLA2-X+/+ mice reconstituted with sPLA2-X-/- bone marrow to a similar extent seen in sPLA2-X+/+ mice.
Conclusions: sPLA2-X in neutrophils plays a critical role in the pathogenesis of abdominal aortic aneurysms.
- © 2011 by American Heart Association, Inc.