title: 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.
  
  
  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.
authors.affiliation: 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.).
authors.forename: Castigliano M
authors.initials: CM
authors.lastname: Bhamidipati
authors.affiliation: 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.).
authors.forename: Carl A
authors.initials: CA
authors.lastname: Whatling
authors.affiliation: 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.).
authors.forename: Gaurav S
authors.initials: GS
authors.lastname: Mehta
authors.affiliation: 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.).
authors.forename: Akshaya K
authors.initials: AK
authors.lastname: Meher
authors.affiliation: 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.).
authors.forename: Vanessa A
authors.initials: VA
authors.lastname: Hajzus
authors.affiliation: 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.).
authors.forename: Gang
authors.initials: G
authors.lastname: Su
authors.affiliation: 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.).
authors.forename: Morgan
authors.initials: M
authors.lastname: Salmon
authors.affiliation: 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.).
authors.forename: Gilbert R
authors.initials: GR
authors.lastname: Upchurch
authors.affiliation: 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.).
authors.forename: Gary K
authors.initials: GK
authors.lastname: Owens
authors.affiliation: 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.
authors.forename: Gorav
authors.initials: G
authors.lastname: Ailawadi
mesh_terms: D000368:Aged; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D001094:Arachidonate 5-Lipoxygenase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D006937:Hypercholesterolemia / Q000150:complications / Q000201:enzymology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D020556:Neutrophil Infiltration; D010196:Pancreatic Elastase / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D018183:Transplantation Chimera / Q000378:metabolism
chemical_list: D016859:Lipoxygenase Inhibitors; D011973:Receptors, LDL; D000804:Angiotensin II; D001094:Arachidonate 5-Lipoxygenase; C583212:ALOX5 protein, human; D010196:Pancreatic Elastase; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: aneurysm; aorta, abdominal; arachidonate 5-lipoxygenase; inflammation; leukotriene B4; lipoxygenase inhibitors