title: Reduction of mouse atherosclerosis by urokinase inhibition or with a limited-spectrum matrix metalloproteinase inhibitor.
abstract: OBJECTIVE
  Elevated activity of urokinase plasminogen activator (uPA) and MMPs in human arteries is associated with accelerated atherosclerosis, aneurysms, and plaque rupture. We used Apoe-null mice with macrophage-specific uPA overexpression (SR-uPA mice; a well-characterized model of protease-accelerated atherosclerosis) to investigate whether systemic inhibition of proteolytic activity of uPA or a subset of MMPs can reduce protease-induced atherosclerosis and aortic dilation.
  
  
  RESULTS
  SR-uPA mice were fed a high-fat diet for 10 weeks and treated either with an antibody inhibiting mouse uPA (mU1) or a control antibody. mU1-treated mice were also compared with PBS-treated non-uPA-overexpressing Apoe-null mice. Other SR-uPA mice were treated with one of three doses of a limited-spectrum synthetic MMP inhibitor (XL784) or vehicle. mU1 reduced aortic root intimal lesion area (20%; P = 0.05) and aortic root circumference (12%; P = 0.01). All XL784 doses reduced aortic root intimal lesion area (22-29%) and oil-red-O-positive lesion area (36-42%; P < 0.05 for all doses and both end points), with trends towards reduced aortic root circumference (6-10%). Neither mU1 nor XL784 significantly altered percent aortic surface lesion coverage. Several lines of evidence identified MMP-13 as a mediator of uPA-induced aortic MMP activity.
  
  
  CONCLUSIONS
  Pharmacological inhibition of either uPA or selected MMPs decreased atherosclerosis in SR-uPA mice. uPA inhibition decreased aortic dilation. Differential effects of both agents on aortic root vs. distal aortic atherosclerosis suggest prevention of atherosclerosis progression vs. initiation. Systemic inhibition of uPA or a subset of MMPs shows promise for treating atherosclerosis.
authors.affiliation: Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Jie Hong
authors.initials: JH
authors.lastname: Hu
authors.affiliation: Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Phanith
authors.initials: P
authors.lastname: Touch
authors.affiliation: Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Jingwan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Wei
authors.affiliation: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Shihui
authors.initials: S
authors.lastname: Liu
authors.affiliation: The Finsen Laboratory, Copenhagen University Hospital and Biotech Research & Innovation Centre, Copenhagen University, Copenhagen, Denmark.
authors.forename: Ida K
authors.initials: IK
authors.lastname: Lund
authors.affiliation: The Finsen Laboratory, Copenhagen University Hospital and Biotech Research & Innovation Centre, Copenhagen University, Copenhagen, Denmark.
authors.forename: Gunilla
authors.initials: G
authors.lastname: Høyer-Hansen
authors.affiliation: Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA ddichek@uw.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Dichek
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D001018:Aortic Diseases / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D004108:Dilatation, Pathologic; D004195:Disease Models, Animal; D008055:Lipids / Q000097:blood; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; D008055:Lipids; D061965:Matrix Metalloproteinase Inhibitors; D015842:Serine Proteinase Inhibitors; D014568:Urokinase-Type Plasminogen Activator; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse
keywords: Atherosclerosis; Matrix metalloproteinases; Mouse models; Protease inhibition; Urokinase