title: Human plasminogen kringle 1-5 reduces atherosclerosis and neointima formation in mice by suppressing the inflammatory signaling pathway.
abstract: BACKGROUND
  Activation of vascular endothelial cells plays an important role in atherogenesis and plaque instability. Recent research has demonstrated that late-stage inhibition of plaque angiogenesis by angiostatin (kringle 1-4) reduces macrophage accumulation and slows the progression of advanced atherosclerosis. Kringle 1-5 (K(1-5)) is a variant of angiostatin that contains the first five kringle domains of plasminogen.
  
  
  OBJECTIVE
  To investigate whether K(1-5) has an inhibitory effect on early-stage atherosclerosis, using the apolipoprotein E (ApoE)-deficient mouse model and a carotid artery ligation model.
  
  
  METHODS
  ApoE-deficient mice received K(1-5) treatment for 4 weeks, and the severity of aortic atherosclerosis was measured. In the ligation model, the left common carotid arteries of C57BL/6 mice were ligated near the carotid bifurcation, and the mice received K(1-5) for 4 weeks. Human umbilical vein endothelial cells were pretreated with K(1-5) before tumor necrosis factor-alpha (TNF-alpha) treatment to explore the anti-inflammatory effect of K(1-5).
  
  
  RESULTS
  The areas of the lesion in the aortas of ApoE-deficient mice that received K(1-5) treatment were notably decreased, and the formation of carotid neointima in the C57BL/6 mice was decreased by treatment with K(1-5). Expression of TNF-alpha-induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 was inhibited by K(1-5) treatment, possibly via downregulation of translocation of nuclear factor-kappaB and expression of reactive oxygen species.
  
  
  CONCLUSIONS
  K(1-5) reduced atherosclerosis and neointima formation in mice, possibly through inhibition of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression in endothelial cells.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: P C
authors.initials: PC
authors.lastname: Chang
authors.forename: H L
authors.initials: HL
authors.lastname: Wu
authors.forename: H C
authors.initials: HC
authors.lastname: Lin
authors.forename: K C
authors.initials: KC
authors.lastname: Wang
authors.forename: G Y
authors.initials: GY
authors.lastname: Shi
mesh_terms: D000818:Animals; D001011:Aorta / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002339:Carotid Arteries / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism; D006801:Humans; D006965:Hyperplasia; D020672:I-kappa B Proteins / Q000378:metabolism; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D010446:Peptide Fragments / Q000008:administration & dosage / Q000378:metabolism*; D010958:Plasminogen / Q000008:administration & dosage / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D017539:Tunica Intima / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C491499:plasminogen kringle 5; D018799:Intercellular Adhesion Molecule-1; D000072000:NF-KappaB Inhibitor alpha; D010958:Plasminogen