title: Temporal and quantitative analysis of expression of metalloproteinases (MMPs) and their endogenous inhibitors in atherosclerotic lesions.
abstract: Matrix metalloproteinases (MMPs) play an important role in the pathogenesis of vascular diseases, such as atherosclerosis, plaque rupture and aneurysms. Although several MMPs have been demonstrated in the lesions of atherosclerosis, their expression profiles during the initiation and progression of lesions have not been fully determined. We hypothesized that the expression of various MMPs, along with their endogenous inhibitors, may be differentially regulated dependent upon the lesion progression. Therefore, we made a temporal and quantitative analysis of the mRNA and protein expression of MMPs and tissue inhibitors of metalloproteinases expressed in the different stages of atherosclerotic lesions of rabbits and humans. We found that MMP-1, MMP-12 and MMP-13 expression was nearly absent in the normal arterial wall, but was remarkably increased with lesion progression. Furthermore, the expression of these MMPs in the lesions was closely associated with intimal macrophages and monocyte chemoattractant protein-1 expression, suggesting that the intimal macrophages are the major source of production of these MMPs. MMP-3 and MT1-MMP were also significantly upregulated in the early-stage lesions and fatty streaks compared to the normal aortas of rabbits. Our results indicate that MMP-1, -12, and -13 derived from intimal macrophages may play a pivotal role in both lesion initiation and progression, and therefore are potential therapeutic targets for the treatment of plaque rupture and aneurysm formation.
authors.affiliation: Department of Molecular Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yu
authors.forename: Tomonari
authors.initials: T
authors.lastname: Koike
authors.forename: Shuji
authors.initials: S
authors.lastname: Kitajima
authors.forename: Enqi
authors.initials: E
authors.lastname: Liu
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Morimoto
authors.forename: Masashi
authors.initials: M
authors.lastname: Shiomi
authors.forename: Kinta
authors.initials: K
authors.lastname: Hatakeyama
authors.forename: Yujiro
authors.initials: Y
authors.lastname: Asada
authors.forename: Ke-Yong
authors.initials: KY
authors.lastname: Wang
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Sasaguri
authors.forename: Teruo
authors.initials: T
authors.lastname: Watanabe
authors.forename: Jianglin
authors.initials: J
authors.lastname: Fan
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015153:Blotting, Western; D018932:Chemokine CCL2 / Q000096:biosynthesis; D018450:Disease Progression; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D008264:Macrophages / Q000378:metabolism; D008297:Male; D045726:Metalloproteases / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019714:Tissue Inhibitor of Metalloproteinases / Q000096:biosynthesis* / Q000235:genetics; D017539:Tunica Intima / Q000166:cytology
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D045726:Metalloproteases