期刊
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
卷 34, 期 12, 页码 2669-2678出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.114.304016
关键词
aneurysm; aorta; abdominal; arachidonate 5-lipoxygenase; inflammation; leukotriene B4; lipoxygenase inhibitors
资金
- AstraZeneca, PLC
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.
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