title: Macrophage metalloelastase accelerates the progression of atherosclerosis in transgenic rabbits.
abstract: BACKGROUND
  Macrophage metalloelastase (matrix metalloproteinase [MMP]-12) is upregulated in atherosclerotic lesions and aneurysm; thus, increased MMP-12 activity may play an important role in the pathogenesis of atherosclerosis. However, the pathological roles of MMP-12 in the initiation and progression of atherosclerosis have not been defined.
  
  
  RESULTS
  We compared the susceptibility of MMP-12 transgenic (Tg) rabbits to cholesterol-rich diet-induced atherosclerosis with that of non-Tg littermate rabbits. The rabbits were maintained at either relatively lower levels of hypercholesterolemia for shorter periods or higher levels of hypercholesterolemia for longer periods through a diet containing different amounts of cholesterol. We found no significant difference in the aortic atherosclerotic lesion size or quality between Tg and non-Tg rabbits at lower hypercholesterolemia. At higher hypercholesterolemia for longer periods, however, Tg rabbits developed more extensive atherosclerosis in the aortas and coronary arteries than did non-Tg rabbits. Histological examinations revealed that atherosclerotic lesions of Tg rabbits contained prominent macrophage infiltration associated with marked disruption of the elastic lamina in the tunica media with occasional formation of aneurysm-like lesions. Furthermore, increased expression of MMP-12 derived from macrophages was associated with elevated expression of MMP-3, suggesting that MMP-12 may play a pivotal role in the cascade activation of other MMPs, thereby exacerbating extracellular matrix degradation during the progression of atherosclerosis.
  
  
  CONCLUSIONS
  Overexpression of MMP-12 causes accelerated atherosclerosis in Tg rabbits. These results suggest that macrophage-derived MMP-12 participates in the progression of atherosclerosis.
authors.affiliation: Department of Pathology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Jingyan
authors.initials: J
authors.lastname: Liang
authors.forename: Enqi
authors.initials: E
authors.lastname: Liu
authors.forename: Ying
authors.initials: Y
authors.lastname: Yu
authors.forename: Shuji
authors.initials: S
authors.lastname: Kitajima
authors.forename: Tomonari
authors.initials: T
authors.lastname: Koike
authors.forename: Yingji
authors.initials: Y
authors.lastname: Jin
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Morimoto
authors.forename: Kinta
authors.initials: K
authors.lastname: Hatakeyama
authors.forename: Yujiro
authors.initials: Y
authors.lastname: Asada
authors.forename: Teruo
authors.initials: T
authors.lastname: Watanabe
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Sasaguri
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Watanabe
authors.forename: Jianglin
authors.initials: J
authors.lastname: Fan
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D050197:Atherosclerosis / Q000209:etiology*; D002465:Cell Movement; D003324:Coronary Artery Disease / Q000201:enzymology; D006801:Humans; D007150:Immunohistochemistry; D008264:Macrophages / Q000502:physiology; D053508:Matrix Metalloproteinase 12; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D020782:Matrix Metalloproteinases / Q000032:analysis; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000032:analysis / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D011817:Rabbits
chemical_list: D020782:Matrix Metalloproteinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020780:Matrix Metalloproteinase 9; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12