Abstract 17186: Inhibition of Extracellular Granzyme B Reduces Abdominal Aortic Aneurysm Rupture
Introduction: Abdominal aortic aneurysm (AAA) is an age-related disease caused by progressive weakening of the vessel wall. Although AAA progression leading to rupture can be fatal, effective pharmacological interventions aimed at halting AAA progression at early stages of disease are not available. Previous work in our laboratory has demonstrated that knocking out the serine protease granzyme B (GZMB) reduces incidence and severity of AAA in mice in a perforin-independent manner. GZMB is well known for its role in eliminating target cells via apoptosis, but also accumulates extracellularly during inflammation and cleaves extracellular matrix (ECM) components such as fibronection and fibrillin−1.
Hypothesis: We hypothesize that GZMB contributes to AAA development via the degradation of vascular extracellular matrix components and that the inhibition of extracellular GZMB will reduce incidence and severity of AAA progression.
Methods: To induce aortic aneurysm, apoE−/− mice were implanted with an osmotic minipump that released angiotensin II (1000 ng/min/kg) for 28 days. Animals were injected with a novel GZMB inhibitor, serpin A3N, (4–120 ug/kg) or saline prior to pump implantation. Tissues were harvested after 28 days. Survival, morphology and ECM composition were evaluated.
Results: A significant dose-dependent reduction in the frequency of aortic rupture was observed in mice that received serpin treatment. Serpin A3N was also shown to prevent decorin cleavage by GZMB in vitro. Immunohistochemical analyses revealed reduced GZMB staining and a corresponding reduction in loss of adventitial decorin in serpin-treated mice while collagen deposition was increased. When compared to controls, adventitial collagen from serpin-treated mice was observed to have significantly thicker fibrils and greater density, suggesting higher tensile strength.
Conclusions: GZMB contributes to the loss of vessel wall integrity in AAA through the cleavage of ECM components. Extracellular inhibition of GZMB prevents degradation of decorin and promotes remodelling of collagen. This reinforcement of the adventitia following medial injury reduces the rate of rupture and improves the overall rate of survival.
- © 2010 by American Heart Association, Inc.