Genetic deficiency of cyclooxygenase-2 attenuates abdominal aortic aneurysm formation in mice.
OBJECTIVE
Abdominal aortic aneurysms (AAAs) are characterized by chronic inflammation which contributes to the remodeling and eventual weakening of the vessel wall. Increased cyclooxygenase-2 (COX-2) expression is detected in human aneurysmal tissue and is suggested to contribute to the disease. The aim of the current study was to define the role of COX-2 expression in the development of AAAs, using a model of the disease.


METHODS
AAAs were induced in mice by chronic angiotensin II infusion, and were analyzed following 3, 7, 21 or 28 days of the infusion. AAA incidence and severity, together with the expression of inflammatory markers, were compared between abdominal aortas from COX-2-deficient mice and their wild-type littermate controls.


RESULTS
The AAA incidence in COX-2 wild-type mice was 54% (13/24), whereas AAAs were not detected in COX-2-deficient mice (0/23) following 28 days of angiotensin II infusion. The genetic deficiency of COX-2 also resulted in a 73% and 90% reduction in AAA incidence following 7 and 21 days of angiotensin II infusion, respectively. In COX-2 wild-type mice, COX-2 mRNA expression in the abdominal aorta was induced by angiotensin II beginning 3 days following initiation of the infusion, which continued throughout progression of the disease. Abundant COX-2 protein expression was detected in medial smooth muscle cells adjacent to the AAAs. The deficiency of COX-2 significantly attenuated mRNA expression in the abdominal aorta of the macrophage marker CD68, and the inflammatory cell recruitment chemokines, monocyte chemotactic protein-1 and macrophage inflammatory protein-1alpha.


CONCLUSIONS
Our findings suggest that increased COX-2 expression in smooth muscle cells of the abdominal aorta contributes to AAA formation in mice by enhancing inflammatory cell infiltration.
Gitlin
Jonathan M
JM
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082, USA.
Trivedi
Darshini B
DB
Langenbach
Robert
R
Loftin
Charles D
CD
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001012:Aorta, Abdominal / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D017544:Aortic Aneurysm, Abdominal / Q000276:immunology / Q000378:metabolism*; D018932:Chemokine CCL2 / Q000378:metabolism; D054407:Chemokine CCL4; D002634:Chemotaxis, Leukocyte; D051546:Cyclooxygenase 2 / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D008565:Membrane Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D023421:Models, Animal; D012333:RNA, Messenger / Q000032:analysis; D013997:Time Factors
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D054407:Chemokine CCL4; D019402:Macrophage Inflammatory Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; D000804:Angiotensin II; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human