Angiotensin II-induced abdominal aortic aneurysm occurs independently of the 5-lipoxygenase pathway in apolipoprotein E-deficient mice.
Genetic association studies and pathological analysis of cardiovascular disease specimens implicate a role for the 5-lipoxygenase (5-LO)/leukotriene (LT) pathway in human cardiovascular disease. Previously, we had detected a role for this pathway in the incidence and severity of hyperlipidemic, cholate-containing, diet-induced aortic aneurysm in mice. The goal of the present study was to assess the importance of the 5-LO/LT pathway in angiotensin II (Ang II)-induced murine abdominal aortic aneurysm (AAA) formation. Mice with either genetic (5-LO(-/-)) or pharmacological (MK-0591) inhibition of the 5-LO pathway on an apolipoprotein E-deficient (apoE(-/-)) background were subjected to a normal chow diet with infusion of Ang II (500 ng/kg/min) for 28 days for assessment of AAA incidence and severity. Ang II-induced marked aortic wall remodeling with an incidence of 32, 29 and 40% AAA formation in 5-LO(-/-) apoE(-/-), 5-LO(+/+)apoE(-/-) and 5-LO(+/+)apoE(-/-) mice treated with FLAP inhibitor MK-0591, respectively, with no statistically significant differences in incidence or severity between groups. Abrogation of the 5-LO pathway in mice indicates a lack of role of leukotrienes in Ang II-induced AAA pathogenesis stressing the need for additional non-rodent AAA pre-clinical models to be tested.
Cao
Richard Yang
RY
Department of Physiology, Queen's University, Kingston, Ont. K7L 3N6, Canada.
Adams
Michael A
MA
Habenicht
Andreas J
AJ
Funk
Colin D
CD
D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000378:metabolism*; D001057:Apolipoproteins E / Q000235:genetics* / Q000502:physiology*; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D001794:Blood Pressure; D054407:Chemokine CCL4; D007211:Indoles / Q000493:pharmacokinetics / Q000494:pharmacology; D007249:Inflammation; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008957:Models, Genetic; D011804:Quinolines / Q000493:pharmacokinetics / Q000494:pharmacology; D013997:Time Factors
D001057:Apolipoproteins E; D054407:Chemokine CCL4; D007211:Indoles; D019402:Macrophage Inflammatory Proteins; D011804:Quinolines; D000804:Angiotensin II; C078266:MK 0591; D001094:Arachidonate 5-Lipoxygenase