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Home > Medical Professionals > Research Initiatives Conference > Poster Abstracts Accepted > Ennis Development Of Elastase-induced Abdominal Aortic Aneurysms

Development Of Elastase-induced Abdominal Aortic Aneurysms In Mice Is Independent Of The 5-lipoxygenase/leukotriene Pathway

Terri L. Ennis, Dongli Mao, Monica Pagano, Robert W. Thompson
Washington University School of Medicine, St. Louis, MO

Objectives: Leukotrienes (LTs) generated by the action of 5-lipoxygenase (5-LO) have been implicated in diet-induced experimental abdominal aortic aneurysms (AAAs), in part through their induction of macrophage inflammatory protein-1alpha (MIP-1a). To determine if this molecular mechanism might be a general feature of aneurysmal degeneration, we examined the role of 5-LO, LTs and MIP-1a in the development of elastase-induced AAAs. Methods: Transient elastase perfusion of the abdominal aorta was used to induce the development of AAAs in adult male C57Bl/6 mice. Aortic diameter (AD) was measured before elastase perfusion and the percent increase in AD was determined after 14 days. Serum and aortic tissue LT levels were measured by ELISA at various time intervals after elastase perfusion. Two-tailed t-tests were used for all between-group comparisons. Results: Wild-type (WT) mice developed AAAs associated with mononuclear inflammation and progressive destruction of medial elastin (overall increase in AD, mean ± SE, 168.5 ± 6.0%; n = 15), accompanied by a 28-fold increase in aortic wall concentration of cysteine-LTs and a 4.8-fold increase in LTB4 on day 7 (both P < 0.05). There was no difference in the extent of aneurysmal dilatation between WT controls and mice with targeted deletion of 5-LO (mean increase in AD 168.7 ± 6.5%, n = 15), nor between WT mice treated with the LT antagonist MK866 and vehicle-treated controls (mean increase in AD: MK866, 170.9 ± 7.7%, n = 11; controls, 185.1 ± 10.4%, n = 11). In contrast, mice with targeted deletion of MIP-1a were actually more susceptible to elastase-induced AAAs than WT controls (mean increase in AD 198.4 ± 7.7%; n = 16; P < 0.01). Conclusions: Increased aortic wall production of LTs accompanies the development of elastase-induced aortic aneurysms, but the extent of aneurysmal degeneration is independent of either 5-LO or LTs and treatment with a LT antagonist does not prevent AAAs. For reasons not yet understood, genetic deficiency in MIP-1a appears to enhance susceptibility to elastase-induced AAAs.