title: Lesional overexpression of matrix metalloproteinase-9 promotes intraplaque hemorrhage in advanced lesions but not at earlier stages of atherogenesis.
abstract: BACKGROUND
  Matrix metalloproteinase-9 (MMP-9) is involved in atherosclerosis and elevated MMP-9 activity has been found in unstable plaques, suggesting a crucial role in plaque rupture. This study aims to assess the effect of MMP-9 on plaque stability in apolipoprotein E-deficient mice at different stages of plaque progression.
  
  
  RESULTS
  Atherosclerotic lesions were elicited in carotid arteries by perivascular collar placement. MMP-9 overexpression in intermediate or advanced plaques was effected by intraluminal incubation with an adenovirus (Ad.MMP-9). A subset was coincubated with Ad.TIMP-1. Mock virus served as a control. Plaques were analyzed histologically. In intermediate lesions, MMP-9 overexpression induced outward remodeling, as shown by a 30% increase in media size (p=0.03). In both intermediate and advanced lesions, prevalence of vulnerable plaque morphology tended to be increased. Half of MMP-9-treated lesions displayed intraplaque hemorrhage, whereas in controls and the Ad.MMP-9/Ad.TIMP-1 group this was 8% and 16%, respectively (p=0.007). Colocalization with neovessels may point to neo-angiogenesis as a source for intraplaque hemorrhage.
  
  
  CONCLUSIONS
  These data show a differential effect of MMP-9 at various stages of plaque progression and suggest that lesion-targeted MMP-9 inhibition might be a valuable therapeutic modality in stabilizing advanced plaques, but not at earlier stages of lesion progression.
authors.affiliation: Division of Biopharmaceutics, Leiden University, Leiden, The Netherlands. r.de.nooijer@chem.leidenuniv.nl
authors.forename: R
authors.initials: R
authors.lastname: de Nooijer
authors.forename: C J N
authors.initials: CJ
authors.lastname: Verkleij
authors.forename: J H
authors.initials: JH
authors.lastname: von der Thüsen
authors.forename: J W
authors.initials: JW
authors.lastname: Jukema
authors.forename: E E
authors.initials: EE
authors.lastname: van der Wall
authors.forename: Thüsen J C
authors.initials: TJ
authors.lastname: van Berkel
authors.forename: A H
authors.initials: AH
authors.lastname: Baker
authors.forename: E A L
authors.initials: EA
authors.lastname: Biessen
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006470:Hemorrhage / Q000378:metabolism* / Q000473:pathology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D012421:Rupture; D012720:Severity of Illness Index
chemical_list: D001057:Apolipoproteins E; D020780:Matrix Metalloproteinase 9