Castigliano M Bhamidipati1, Carl A Whatling1, Gaurav S Mehta1, Akshaya K Meher1, Vanessa A Hajzus1, Gang Su1, Morgan Salmon1, Gilbert R Upchurch1, Gary K Owens1, Gorav Ailawadi2. 1. From the Division of Thoracic and Cardiovascular Surgery, Department of Surgery (C.M.B., A.K.M., V.A.H., G.A.), Department of Surgery (G.S.M.), Division of Vascular and Endovascular Surgery, Department of Surgery (G.S., G.R.U.), Department of Molecular Physiology and Biological Physics (M.S., G.K.O.), Department of Molecular Physiology and Biological Physics, Robert M. Berne Cardiovascular Research Center (G.R.U., G.K.O., G.A.), and Department of Biomedical Engineering (G.A.), University of Virginia School of Medicine, Charlottesville; and Cardiovascular Disease Section, Bioscience Department, AstraZeneca R&D, Mölndal, Sweden (C.A.W.). 2. From the Division of Thoracic and Cardiovascular Surgery, Department of Surgery (C.M.B., A.K.M., V.A.H., G.A.), Department of Surgery (G.S.M.), Division of Vascular and Endovascular Surgery, Department of Surgery (G.S., G.R.U.), Department of Molecular Physiology and Biological Physics (M.S., G.K.O.), Department of Molecular Physiology and Biological Physics, Robert M. Berne Cardiovascular Research Center (G.R.U., G.K.O., G.A.), and Department of Biomedical Engineering (G.A.), University of Virginia School of Medicine, Charlottesville; and Cardiovascular Disease Section, Bioscience Department, AstraZeneca R&D, Mölndal, Sweden (C.A.W.). gorav@virginia.edu.
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.
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. HumanAAA 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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