Abstract 86: Apo(a) Inhibits Plasminogen-Dependent Abdominal Aortic Aneurysm Formation in Transgenic Mice
Abdominal Aortic Aneurysm (AAA) is a lethal disorder found primarily in adults over 65. Unlike coronary heart disease, the incidence of AAA is rapidly increasing, and currently there is no nonsurgical treatment. AAA is a chronic inflammatory disease that includes early leukocyte infiltration, destruction of the elastic lamina and extracellular matrix, expansion of the aorta, and eventually fatal aorta rupture. Components of the plasminogen (Plg) and MMP pathways that mediate leukocyte infiltration are prominent in AAA. The goal of this study is to investigate regulators of these pathways in AAA, namely the inhibition Plg by apo(a). In AAA patients, the association of elevated Lp(a) and progression of AAA is controversial. Apolipoprotein(a) [apo(a)], a component of lipoprotein(a) [Lp(a)], has a high homology to Plg, and interferes with Plg functions in vitro. In our previous studies apo(a), independent of Plg, inhibited neutrophil recruitment in a peritonitis model of inflammation, and in Plg deficient mice macrophage infiltration was impaired in CaCl2 induced AAA formation. Our hypothesis is that apo(a) inhibits AAA formation by reducing neutrophil or macrophage infiltration by interfering with Plg. To test our hypothesis, the CaCl2 induced AAA model was performed in 5 strains of mice: WT; Plg-/-; apo(a)tg; apo(a)tg:Plg-/-; and Lp(a)tg mice (6-14 mice analyzed per genotype). Three weeks after injury, the WT aorta diameter increased from 0.54 to 0.88mm (62%). The diameter changed in WT 0.31±0.11mm, apo(a)tg 0.06±0.02mm, apo(a):Plg-/- 0.39±0.07mm and Lp(a) 0.08±0.07mm. The dilation was significantly lower in apo(a) and Lp(a) mice compared to WT (P<0.001). The H&E, Trichrome and EVG stain showed elevated leukocyte infiltration in WT and apo(a):Plg-/- injured aorta, accompanied by thining of the media layer and elastic lamellae fragmentation. In contrast, the aorta of apo(a) mice remained preserved. Neutrophils and macrophages were decreased in apo(a) mice compared to WT(P<0.05). In apo(a):Plg-/- mice, only neutrophil infiltration was decreased not macrophages. These results suggest that inhibition of neutrophils in apo(a) mice is independent of Plg, but reduced macrophage infiltration in apo(a) mice is Plg-dependent during AAA formation.
- © 2012 by American Heart Association, Inc.