Expression of neutrophil collagenase (matrix metalloproteinase-8) in human atheroma - A novel collagenolytic pathway suggested by transcriptional profiling

Article

关键词: HUMAN ATHEROSCLEROTIC PLAQUES;    ACUTE CORONARY SYNDROMES;    SUBSTRATE-SPECIFICITY;    GENE-EXPRESSION;    ACTIVE ENZYME;    IN-VIVO;    LESIONS;    LOCALIZATION;    MACROPHAGE;    REGIONS;   

DOI  :  10.1161/hc4101.097419

来源: SCIE

【 摘 要 】

Background-Loss of interstitial collagen, particularly type I collagen, the major load-bearing molecule of atherosclerotic plaques, renders atheroma prone to rupture. Initiation of collagen breakdown requires interstitial collagenases, a matrix metalloproteinase (MMP) subfamily consisting of MMP-1, MMP-8, and MMP-13. Previous work demonstrated the overexpression of MMP-1 and MMP-13 in human atheroma. However, no study has yet evaluated the expression of MMP-8, known as neutrophil collagenase, the enzyme that preferentially degrades type I collagen, because granulocytes do not localize in plaques. Methods and Results-Transcriptional profiling and reverse transcription-poly me rase chain reaction analysis revealed inducible expression of MMP-8 transcripts in CD40 ligand-stimulated mononuclear phagocytes. Western blot analysis demonstrated that 3 atheroma-associated cell types, namely, endothelial cells, smooth muscle cells, and mononuclear phagocytes, expressed MMP-8 in vitro upon stimulation with proinflammatory cytokines such as interleukin-1 beta, tumor necrosis factor-alpha, or CD40 ligand. MMP-8 protein elaborated from these atheroma-associated cell types migrated as 2 immunoreactive bands, corresponding to the molecular weights of the zymogen and the active molecule. Extracts from atherosclerotic, but not nondiseased arterial tissue, contained similar immunoreactive bands. Moreover, all 3 cell types expressed MMP-8 mRNA and protein in human atheroma in situ. Notably. MMP-8 colocalized with cleaved but not intact type I collagen within the shoulder region of the plaque, a frequent site of rupture. Conclusions-These data point to MMP-8 as a previously unsuspected participant in collagen breakdown, an important determinant of the vulnerability of human atheroma.

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