title: Plaque oxysterols induce unbalanced up-regulation of matrix metalloproteinase-9 in macrophagic cells through redox-sensitive signaling pathways: Implications regarding the vulnerability of atherosclerotic lesions.
abstract: An imbalance in the matrix metalloproteinases/tissue inhibitors of metalloproteinases (MMPs/TIMPs) contributes to atherosclerotic plaque destabilization and rupture. Here we determined whether oxysterols accumulating in advanced atherosclerotic lesions play a role in plaque destabilization. In human promonocytic U937 cells, we investigated the effects of an oxysterol mixture of composition similar to that in advanced human carotid plaques on the expression and synthesis of MMP-9 and its endogenous inhibitors TIMP-1 and TIMP-2. A marked increment of MMP-9 gene expression, but not of its inhibitors, was observed by real-time RT-PCR; MMP-9 gelatinolytic activity was also found increased by gel zymography. Consistently, a net increment of MMP-9 protein level was also observed by immunoblotting. Using antioxidants or specific inhibitors or siRNAs, we demonstrated that the oxysterol mixture induces MMP-9 expression through: (i) overproduction of reactive oxygen species, probably by NADPH-oxidase and mitochondria; (ii) up-regulation of mitogen-activated protein kinase signaling pathways via protein kinase C; and (iii) up-regulation of activator protein-1- and nuclear factor-κB-DNA binding. These results suggest, for the first time, that oxysterols accumulating in advanced atherosclerotic lesions significantly contribute to plaque vulnerability by promoting MMP-9/TIMP-1/2 imbalance in phagocytic cells.
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Torino, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Gargiulo
authors.forename: Barbara
authors.initials: B
authors.lastname: Sottero
authors.forename: Paola
authors.initials: P
authors.lastname: Gamba
authors.forename: Elena
authors.initials: E
authors.lastname: Chiarpotto
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Poli
authors.forename: Gabriella
authors.initials: G
authors.lastname: Leonarduzzi
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D002460:Cell Line; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D058226:Plaque, Atherosclerotic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D011493:Protein Kinase C / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013261:Sterols / Q000378:metabolism / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
chemical_list: D000975:Antioxidants; D016328:NF-kappa B; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D013261:Sterols; D018808:Transcription Factor AP-1; D011493:Protein Kinase C; D020780:Matrix Metalloproteinase 9