Abstract 1461: Stabilization of Extracellular Matrix Antagonizes Proinflammatory Signaling and Prevents Progression of Aortic Aneurysm In Vivo
We and others reported that proinflammatory signaling in aortic wall enhances degradation of extracellular matrix (ECM) and, at the same time, impairs ECM biosynthesis, leading to the destabilization of aortic tissue and progression of abdominal aortic aneurysm (AAA). However, it is not known if the stability of ECM affects the proinflammatory signaling during AAA progression. We hypothesize that stabilization of ECM prevents the progression of AAA not only by reinforcing aortic tissue but also by reducing proinflammatory signaling. To this end, we examined the role of lysyl oxidase (LOX), a cross-linking enzyme that stabilizes collagen and elastin fibers, during the progression of AAA. We created mouse AAA model by abluminal application of CaCl2. Local LOX activity decreased below the basal level from 3 to 5 weeks after CaCl2 treatment. To enhance ECM stabilization, we performed LOX gene transfer by abluminal application of adenoviral vector at 3 weeks after CaCl2 treatment. Aortic morphometry demonstrated that the aortic diameters in LOX group were significantly smaller than those in LacZ group at 6 weeks after CaCl2 treatment (LOX; 1.07 ± 0.21 mm, LacZ; 1.45 ± 0.12 mm, p<0.01). Histological analysis of the aorta showed much less ECM disruption in LOX group compared to LacZ group. Interestingly, the aorta in LOX group showed much less cellular infiltration in the periaortic tissue with fewer macrophages. Therefore, we tested the effect of LOX on the production of monocyte chemoattractant protein-1 (MCP-1), a chemokine implicated in AAA development, in rat aortic vascular smooth muscle cells (VSMCs) in culture. VSMCs transfected with LOX secreted significantly less amount of MCP-1 compared to LacZ-transfected VSMCs after stimulation by angiotensin II, which is known to induce MCP-1. In addition, specific inhibition of LOX activity by beta-aminopropionitrile caused substantial enhancement of MCP-1 secretion from VSMCs stimulated with angiotensin II. These findings indicate that ECM stabilization with LOX prevents progression of AAA by suppression of MCP-1 and inflammatory cell infiltration, suggesting a novel antagonistic effect of ECM stabilization on proinflammatory signaling in the pathogenesis of AAA.