© 2001 by European Society of Cardiology
Copyright © 2001, European Society of Cardiology
Inhibition of transcription factor NF-
B reduces matrix metalloproteinase-1, -3 and -9 production by vascular smooth muscle cells
aBristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Bristol BS2 8HW, UK
bDepartment of Medicine and Therapeutics, University of Glasgow, Glasgow, G11 6NT, UK
* Corresponding author. Tel.: +44-1179-283-582; fax: +44-1179-283-581 mark.bond{at}bristol.ac.uk a.newby{at}bristol.ac.uk
Objective: Matrix metalloproteinases (MMPs) contribute to the destruction of the extracellular matrix at the shoulder regions of atherosclerotic plaques that leads to plaque destabilisation and triggers clinical cardiovascular disease. There is therefore considerable interest in establishing the mechanisms responsible for increased MMP production. MMPs-1, -3 and -9 are upregulated by inflammatory cytokines and growth factors that are produced by plaque resident macrophages and smooth muscle cells. Our present studies focused on NF-
B, which regulates numerous inflammatory genes, and is activated in plaque smooth muscle cells. Moreover, an NF-B binding site is present in the promoter of the MMP-9 gene and an NF-B-like element in the promoter of the MMP-1 gene. Methods: We used adenovirus mediated overexpression of its inhibitor, IB
to investigate the role of NF-B in regulation of MMP-1, -3 and -9 by isolated, cytokine stimulated rabbit aortic and human saphenous vein VSMC. Results: IL-1 potently activated NF-B in VSMCs and acted synergistically with growth factors to upregulate expression of MMP-1, -3 and -9. Overexpression of IB, almost completely inhibited expression of MMP-1, -3 and -9 in response to IL-1 alone or in combination with bFGF and PDGF. Conclusion: NF-B is required for cytokine upregulation of MMP-1, -3 and -9 in VSMCs, which suggests that NF-B inhibition may promote plaque stabilisation.
KEYWORDS bFGF, basic fibroblast growth factor; EMSA, electromobility shift assay; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; IL-1, interleukin-1; MMP, matrix metalloproteinase; PDGF, platelet derived growth factor; TNF-, tumour necrosis factor-
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