Indomethacin prevents elastase-induced abdominal aortic aneurysms in the rat

Perfusion of the rat abdominal aorta with elastase induces abdominal aortic aneurysms (AAA), in which the development of aortic dilatation correlates with the influx of inflammatory cells, increased production of matrix metalloproteinases (MMPs), and destruction of medial elastin. We tested the hypothesis that indomethacin, an inhibitor of macrophage MMP expression, might attenuate aneurysmal degeneration in this model. Fourteen adult male Wistar rats underwent 2-hr aortic perfusion with elastase. Six animals received injections of saline and eight animals received 4 mg/kg/day indomethacin for 7 days. Pre-perfusion, post-perfusion, and final aortic diameters (AD) were determined, and histology and substrate gel zymography were performed. Five out of six control animals developed AAA, while no aneurysms were observed in the indomethacin-treated group (P < 0.01). Whereas AD increased 126 +/- 16% in control animals, the mean increase in the indomethacin-treated group was only 56 +/- 6% (P < 0.001). Although animals in both groups demonstrated an inflammatory response dominated by macrophages, the marked destruction of medial elastin in the control group was not present in the treatment group. In addition, substrate zymography demonstrated decreased levels of MMP-9 in animals treated with indomethacin. Indomethacin inhibits aneurysm growth in this model, and the data suggest that it does so by decreasing macrophage expression of at least one elastolytic metalloproteinase, MMP-9.