5-Lipoxygenase Pathway in Experimental Abdominal Aortic Aneurysms

Abstract

Objective— The impact of leukotriene production by the 5-lipoxygenase (5-LO) pathway in the pathophysiology of abdominal aortic aneurysms (AAAs) has been debated. Moreover, a clear mechanism through which 5-LO influences AAA remains unclear. Approach and Results— Aneurysm formation was attenuated in 5-LO –/– mice, and in lethally irradiated wild-type mice reconstituted with 5-LO –/– bone marrow in an elastase perfusion model. Pharmacological inhibition of 5-LO–attenuated aneurysm formation in both aortic elastase perfused wild-type and angiotensin II–treated LDLr –/– (low-density lipoprotein receptor) mice, with resultant preservation of elastin and fewer 5-LO and MMP9 (matrix metalloproteinase)-producing cells. Separately, analysis of wild-type mice 7 days after elastase perfusion showed that 5-LO inhibition was associated with reduced polymorphonuclear leukocyte infiltration to the aortic wall. Importantly, 5-LO inhibition initiated 3 days after elastase perfusion in wild-type mice arrested progression of small AAA. Human AAA and control aorta corroborated these elastin and 5-LO expression patterns. Conclusions— Inhibition of 5-LO by pharmacological or genetic approaches attenuates aneurysm formation and prevents fragmentation of the medial layer in 2 unique AAA models. Administration of 5-LO inhibitor in small AAA slows progression of AAA. Targeted interruption of the 5-LO pathway is a potential treatment strategy in AAA.