Abstract 16320: Role of High Mobility Group Box 1 Protein Expression in the Development of Experimental Abdominal Aortic Aneurysm
Background: Abdominal aortic aneurysm (AAA) expansion is characterized by widespread transmural inflammation and extracellular matrix degradation. High mobility group box1 protein (HMGB1) is one of the recently defined damage-associated molecular pattern molecules derived from necrotic and activated inflammatory cells, and functions as a proinflammatory mediator. However, the role of HMGB1 in the development of AAA is unknown.
Methods and Results: We obtained human aortic wall samples (n=5) during surgical repair of AAA. Autopsy samples from aortic wall were served as control (n=5). Immunohistochemistry showed that HMGB1 was highly expressed in the infiltrated inflammatory cells in the aortic wall of AAA compared with control samples. Next, experimental AAA model was induced in male mice by application of CaCl2 to the infrarenal aorta. Neutralizing anti-HMGB1 antibodies (10mg/kg/day, AAA/antiH, n=10) or control antibodies (AAA/C, n=10) were injected intraperitonealy every 3 days for 4 weeks. Sham-operated mice served as controls (n=10). Immunoblotting showed that HMGB1 expression was increased in AAA/C compared with those in sham (2.3 fold increase, p=0.007). HMGB1 expression was positively correlated with matrix metalloproteinase (MMP)-2 and -9 activity in AAA tissue (all p<0.0001). HMGB1 expression was localized in macrophages, smooth muscle cells, and fibroblasts by immunohistochemistry. Treatment with anti-HMGB1 antibody significantly suppressed AAA formation (1.3±0.1 vs 0.9±0.2 mm, p=0.0005). Elastin von Gieson staining showed that elastin fragmentation was observed in AAA/C, but was attenuated in AAA/antiH. HMGB1 blockade markedly reduced MMP-2 and -9 activity (p<0.0001, p=0.001) and the number of infiltrated macrophages (p=0.008) in the periaoritc tissues. The mRNA level of TNF-α, MCP-1, and CD68 were also reduced in AAA/antiH compared with AAA/C (all p<0.05).
Conclusions: Elevation of HMGB1 level was observed in human AAA and experimental model of AAA. HMGB1 blockade prevented AAA development, in association with reduced inflammatory cytokines expression, infiltration of inflammatory cells, and MMPs activity, and preserved ECM structure. These findings suggest a significant role of HMGB1 in the pathogenesis of AAA.
- © 2010 by American Heart Association, Inc.