Abstract 9779: Abdominal Aortic Aneurysm Formation was Suppressed by an Agonist for α7 Nicotinic Acetylcholine Receptor via NF-kB Inactivation
Background: Previously we reported that activation of vagal nerve by acetylcholinesterase inhibitors attenuated atherogenesis via suppression of inflammatory responses. α7 nicotinic acetylcholine receptor (nAchR) plays an important role in vagal nerve activation. We sought to determine whether AR-R17779, a selective agonist of α7 nAchR, affects the development of abdominal aortic aneurysm (AAA).
Methods and Results: AAA was induced by topical application of calcium chloride (CaCl2) to abdominal aorta (AAA group). NaCl (0.9%) was substituted for CaCl2 as a sham operation (SHAM group). AR-R17779 was administered in drinking water (AAA/AR-R group). One and 6 weeks after the operation, aortic tissue was excised for histological and molecular analyses. Aortic diameter and macrophage infiltration into the aortic adventitia were increased in AAA group compared with SHAM group at 6 weeks. Treatment with AR-R17779 reduced the diameter of the aorta (0.73±0.10 mm vs. 1.07±0.15 mm in AAA, p<0.01) and macrophage infiltration compared with AAA group. Wavy morphology of the elastic lamellae was lost in AAA group while it was preserved in AAA/AR-R group. Expression of inflammatory cytokines (IL-1β, IL-6, MCP-1) and matrix metalloproteinase (MMP)-2 and 9 activities were enhanced in AAA group, which was suppressed in AAA/AR-R group. AR-R17779 treatment suppressed CaCl2-induced expression of cytokines, activities of MMPs and NF-κB activation (p65 phosphorylation) at 1 week when aortic dilatation had not been developed.
Conclusion: Treatment with AR-R17779 prevented the enlargement of abdominal aorta induced by CaCl2 in association with reduced inflammation and extracellular matrix disruption via NF-kB inactivation. These findings suggest a therapeutic potential of α7nAchR activation for prevention of AAA development.
Author Disclosures: H. Kojima: None. T. Tokunou: Employment; Significant; Actelion Pharmaceuticals Japan. Research Grant; Significant; Mitsubishi Tanabe Pharma. A. Watanabe: None. T. Ichiki: None. K. Sunagawa: None.
- © 2015 by American Heart Association, Inc.