5-Lipoxygenase pathway in experimental abdominal aortic aneurysms.
5-Lipoxygenase pathway in experimental abdominal aortic aneurysms.
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DOI：
10.1161/atvbaha.114.304016
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发表时间：
2014-12
期刊：
影响因子：
--
通讯作者：
Ailawadi G
中科院分区：
文献类型：
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作者：
Bhamidipati CM;Whatling CA;Mehta GS;Meher AK;Hajzus VA;Su G;Salmon M;Upchurch GR Jr;Owens GK;Ailawadi G
在腹主动脉瘤（AAA）的病理生理学中，5-脂氧合酶（5-LO）途径产生的白三烯的影响一直存在争议。此外，5-LO影响AAA的明确机制仍不清楚。在5-LO−/−小鼠和在弹性蛋白酶灌注模型中用5-LO−/−骨髓重建的致死性辐照WT小鼠中，动脉瘤形成减弱。在主动脉弹性蛋白酶灌注的WT和血管紧张素II处理的LDLr−/−小鼠中，5-LO的药理学抑制均减弱了动脉瘤形成，从而保留了弹性蛋白和较少的5-LO和MMP 9产生细胞。另外，弹性蛋白酶灌注后7天对WT小鼠的分析表明，5-LO抑制与多形核白细胞浸润到主动脉壁的减少有关。重要的是，在WT小鼠中弹性蛋白酶灌注后3天开始的5-LO抑制阻止了小AAA的进展。人AAA和对照主动脉证实了这些弹性蛋白和5-LO表达模式。在两种独特的AAA模型中，通过药理学或遗传学方法抑制5-LO可减弱动脉瘤形成并防止中层碎裂。在小AAA中施用5-LO抑制剂减缓AAA的进展。靶向阻断5-LO通路是AAA的潜在治疗策略。
The impact of leukotriene production by the 5-Lipoxygenase (5-LO) pathway in the pathophysiology of Abdominal Aortic Aneurysms (AAA) has been debated. Moreover, a clear mechanism through which 5-LO influences AAA remains unclear. Aneurysm formation was attenuated in 5-LO−/− mice, and in lethally irradiated WT mice reconstituted with 5-LO−/− bone marrow in an elastase perfusion model. Pharmacologic inhibition of 5-LO attenuated aneurysm formation in both aortic elastase perfused WT and angiotensin II treated LDLr−/− mice, with resultant preservation of elastin and fewer 5-LO and MMP9 producing cells. Separately, analysis of WT 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 WT mice arrested progression of small AAA. Human AAA and control aorta corroborated these elastin and 5-LO expression patterns. Inhibition of 5-LO by pharmacologic or genetic approaches attenuates aneurysm formation and prevents fragmentation of the medial layer in two 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.