Inhibition of prostaglandin E2 synthesis in abdominal aortic aneurysms -: Implications for smooth muscle cell viability, inflammatory processes, and the expansion of abdominal aortic aneurysms

Background-There is no treatment proven to limit the growth of abdominal aortic aneurysms, in which the histological hallmarks include inflammation and medial atrophy, with apoptosis of smooth muscle cells and destruction of elastin. Methods and Results-Aneurysm biopsies were used for explant cultures, the preparation of smooth muscle cell cultures, and isolation of macrophages. Tissue macrophages stained strongly for cyclooxygenase 2. Prostaglandin E-2 (PGE(2)) concentrations in aneurysm tissue homogenates, conditioned medium from explants, and isolated macrophages were 49 +/- 22 ng/g, 319 +/- 38 ng/mL, and 22 +/- 21 ng/mL, respectively. PGE(2) inhibited DNA synthesis and proliferation in normal aortic smooth muscle cells (IC50, 23.2 +/- 3.8 and 23.6 +/- 4.5 ng/mL, respectively). In smooth muscle cells derived from aneurysmal aorta, PGE(2) also caused cell death, with generation of oligonucleosomes. Conditioned medium from the mixed smooth muscle and monocyte cultures derived from explants also had potent growth-inhibitory effects, and fractionation of this medium showed that the growth-inhibitory molecule(s) coeluted with PGE(2). In explants, indomethacin 10 mu mol/L or mefenamic acid 10 mu mol/L abolished PGE(2) secretion and significantly reduced LL-1 beta and IL-6 secretion. In a separate case-control study, the expansion of abdominal aortic aneurysms was compared in 15 patients taking nonsteroidal anti-inflammatory drugs and 63 control subjects; median growth rates were 1.5 and 3.2 mm/y, respectively, P = 0.001. Conclusions The adverse effects of PGE(2) on aortic smooth muscle cell viability and cytokine secretion in vitro and the apparent effect of anti-inflammatory drugs to lower aneurysm growth rates suggest that selective inhibition of PGE(2) synthesis could be an effective treatment to curtail aneurysm expansion.