title: Activation of inducible nitric oxide synthase increases MMP-2 and MMP-9 levels in ApoE-knockout mice.
abstract: OBJECTIVE
  Atheroma with reduced collagen content becomes fragile, but the underlying mechanisms have not been established. We investigated the influence of inducible nitric oxide synthase (iNOS) induction upon matrix metalloproteinases (MMP)s and collagen content in atheroma.
  
  
  RESULTS
  ApoE-/- x iNOS-/- double knockout and ApoE-/- x iNOS+/+ mice were fed a high-cholesterol diet for 15 weeks. Large atheromatous lesions of comparable size appeared in the roof of the aorta in both strains. Induction of iNOS mRNA was observed only in the atheroma of the ApoE-/-/iNOS+/+ mice. Collagen content was sparse and fat droplets were increased. Gelatin zymography and in situ zymography showed that pro- and active forms of MMP-2 and MMP-9 were more strongly expressed in ApoE-/-/iNOS+/+ than in ApoE-/-/iNOS-/- mice, nitrotyrosine and MMP-9 were co-expressed in the atheroma.
  
  
  CONCLUSIONS
  We conclude that induction of iNOS in atheroma of high-cholesterol-fed ApoE-/-/iNOS+/+ mice leads to increased production and activation of MMPs, with a subsequent decrease in collagen content, affording fragile plaque.
authors.affiliation: Dept. of Physiology, School of Medicine, Tokai University, Isehara, Japan.
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Aratani
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Osawa
authors.forename: Naoto
authors.initials: N
authors.lastname: Fukuyama
authors.forename: Chizuko
authors.initials: C
authors.lastname: Tsuji
authors.forename: Hiroe
authors.initials: H
authors.lastname: Nakazawa
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics / Q000502:physiology*; D002791:Cholesterol, Dietary / Q000008:administration & dosage*; D003094:Collagen / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation; D007150:Immunohistochemistry; D008055:Lipids / Q000097:blood; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D058226:Plaque, Atherosclerotic / Q000201:enzymology* / Q000209:etiology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001057:Apolipoproteins E; D002791:Cholesterol, Dietary; D008055:Lipids; D003094:Collagen; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse