(Circulation. 1999;100:48-54.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Inhibition of Prostaglandin E2 Synthesis in Abdominal Aortic Aneurysms
Implications for Smooth Muscle Cell Viability, Inflammatory Processes, and the Expansion of Abdominal Aortic Aneurysms
From the Department of Vascular Surgery at Charing Cross and the Department of Clinical Pharmacology at Hammersmith Imperial College School of Medicine (G.W.T.), London, UK.
Correspondence to J.T. Powell, Vascular Surgery, Charing Cross Hospital, Fulham Palace Rd, London W6 8RF, UK. E-mail j.powell{at}ic.ac.uk
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 E2 (PGE2) 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. PGE2 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, PGE2 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 PGE2. In explants, indomethacin 10 µmol/L or mefenamic acid 10 µmol/L abolished PGE2 secretion and significantly reduced IL-1ß 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 PGE2 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 PGE2 synthesis could be an effective treatment to curtail aneurysm expansion.
Key Words: aorta • aneurysm • prostaglandins • indomethacin • cyclooxygenase
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