Indomethacin inhibits expansion of experimental aortic aneurysms via inhibition of the cox2 isoform of cyclooxygenase

M. Miralles, W. Wester, G. A. Sicard, R. Thompson, J. M. Reilly, T. Baxter, W. Pearce, J. Hollett, H. Greisler

Research output: Contribution to journalArticle

78 Citations (Scopus)

Abstract

Purpose: Cyclooxygenase, either the cox1 or cox2 isoform, controls synthesis of prostaglandin E 2 (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. Conclusion: Indomethacin attenuates aneurysm growth, and its effects are mediated via inhibition of the cox2 isoform of cyclooxygenase, which decreases PGE2 and MMP-9 synthesis.

Original languageEnglish (US)
Pages (from-to)884-893
Number of pages10
JournalJournal of vascular surgery
Volume29
Issue number5
DOIs
StatePublished - Jan 1 1999

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Aortic Aneurysm
Prostaglandin-Endoperoxide Synthases
Indomethacin
Protein Isoforms
Pancreatic Elastase
Metalloproteases
Prostaglandins E
Aneurysm
Perfusion
Macrophages
Cyclooxygenase Inhibitors
Elastin
Organ Culture Techniques
Culture Media
Aorta
Animal Models
Gels
Enzyme-Linked Immunosorbent Assay
Immunohistochemistry
Control Groups

ASJC Scopus subject areas

  • Surgery
  • Cardiology and Cardiovascular Medicine

Cite this

Indomethacin inhibits expansion of experimental aortic aneurysms via inhibition of the cox2 isoform of cyclooxygenase. / Miralles, M.; Wester, W.; Sicard, G. A.; Thompson, R.; Reilly, J. M.; Baxter, T.; Pearce, W.; Hollett, J.; Greisler, H.

In: Journal of vascular surgery, Vol. 29, No. 5, 01.01.1999, p. 884-893.

Research output: Contribution to journalArticle

Miralles, M, Wester, W, Sicard, GA, Thompson, R, Reilly, JM, Baxter, T, Pearce, W, Hollett, J & Greisler, H 1999, 'Indomethacin inhibits expansion of experimental aortic aneurysms via inhibition of the cox2 isoform of cyclooxygenase', Journal of vascular surgery, vol. 29, no. 5, pp. 884-893. https://doi.org/10.1016/S0741-5214(99)70216-8
Miralles, M. ; Wester, W. ; Sicard, G. A. ; Thompson, R. ; Reilly, J. M. ; Baxter, T. ; Pearce, W. ; Hollett, J. ; Greisler, H. / Indomethacin inhibits expansion of experimental aortic aneurysms via inhibition of the cox2 isoform of cyclooxygenase. In: Journal of vascular surgery. 1999 ; Vol. 29, No. 5. pp. 884-893.
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abstract = "Purpose: Cyclooxygenase, either the cox1 or cox2 isoform, controls synthesis of prostaglandin E 2 (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. Conclusion: Indomethacin attenuates aneurysm growth, and its effects are mediated via inhibition of the cox2 isoform of cyclooxygenase, which decreases PGE2 and MMP-9 synthesis.",
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T1 - Indomethacin inhibits expansion of experimental aortic aneurysms via inhibition of the cox2 isoform of cyclooxygenase

AU - Miralles, M.

AU - Wester, W.

AU - Sicard, G. A.

AU - Thompson, R.

AU - Reilly, J. M.

AU - Baxter, T.

AU - Pearce, W.

AU - Hollett, J.

AU - Greisler, H.

PY - 1999/1/1

Y1 - 1999/1/1

N2 - Purpose: Cyclooxygenase, either the cox1 or cox2 isoform, controls synthesis of prostaglandin E 2 (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. Conclusion: Indomethacin attenuates aneurysm growth, and its effects are mediated via inhibition of the cox2 isoform of cyclooxygenase, which decreases PGE2 and MMP-9 synthesis.

AB - Purpose: Cyclooxygenase, either the cox1 or cox2 isoform, controls synthesis of prostaglandin E 2 (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. Conclusion: Indomethacin attenuates aneurysm growth, and its effects are mediated via inhibition of the cox2 isoform of cyclooxygenase, which decreases PGE2 and MMP-9 synthesis.

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