Indomethacin inhibits expansion of experimental aortic aneurysms via inhibition of the cox2 isoform of cyclooxygenase.
OBJECTIVE
Cyclooxygenase, either the cox1 or cox2 isoform, controls synthesis of prostaglandin E2 (PGE2), which regulates expression of matrix metalloprotease-9 (MMP-9). PGE2 and MMP-9 are elevated in aortic aneurysms. The mechanisms and time course of the inhibition of aneurysm expansion with a nonspecific cyclooxygenase inhibitor, indomethacin, were determined in an animal model.


METHODS
Rats underwent aortic perfusion with saline (n = 40) as controls or with elastase. Elastase-treated animals received no treatment (n = 82) or received indomethacin (n = 73). Aortic diameters were determined at the time of aortic perfusion and when the rats were killed. The aortas were harvested and used for whole organ culture, substrate gel zymography, or histologic analysis.


RESULTS
The control group demonstrated little change in aortic diameter. All the elastase-only animals developed aneurysms (maximal aortic diameter, 5.27 +/- 2.37 mm on day 14). Indomethacin markedly decreased the rate of aortic expansion (maximum aortic diameter, 3.45 +/- 1.11 mm; P <.001 vs the elastase-only group). The enzyme-linked immunosorbent assay of aortic explant culture media showed that PGE2 synthesis paralleled aortic expansion, and indomethacin decreased PGE2 synthesis. Histologically, the aortic elastin architecture was destroyed in the elastase group, but was preserved with indomethacin treatment. In situ, hybridization for cox1 and cox2 showed that cox2, but not cox1, was expressed and was co-localized by immunohistochemistry to macrophages associated with the aortic wall. Decreased levels of MMP-9 activity with indomethacin were shown by means of substrate zymography. MMP-9 was also localized to macrophages.


CONCLUSIONS
Indomethacin attenuates aneurysm growth, and its effects are mediated via inhibition of the cox2 isoform of cyclooxygenase, which decreases PGE2 and MMP-9 synthesis.
Miralles
M
M
Department of Surgery, Washington University School of Medicine and John Cochran Veterans Administration Medical Center, St Louis, MO, USA.
Wester
W
W
Sicard
G A
GA
Thompson
R
R
Reilly
J M
JM
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017544:Aortic Aneurysm, Abdominal / Q000473:pathology*; D017364:Collagenases / Q000378:metabolism; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9; D010544:Peroxidases / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D010544:Peroxidases; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D017364:Collagenases; D020780:Matrix Metalloproteinase 9; D007213:Indomethacin