Inhibition of transcription factor NF-kappa B reduces matrix metalloproteinase-1,-3 and-9 production by vascular smooth muscle cells

Objective: Matrix metalloproteinases (MMPs) contribute to the destruction o f the extracellular matrix at the shoulder regions of atherosclerotic plaqu es that leads to plaque destabilisation and triggers clinical cardiovascula r disease. There is therefore considerable interest in establishing the mec hanisms responsible for increased MMP production. MMPs-1, -3 and -9 are upr egulated by inflammatory cytokines and growth factors that are produced by plaque resident macrophages and smooth muscle cells. Our present studies fo cused an NF-kappaB, which regulates numerous inflammatory genes, and is act ivated in plaque smooth muscle cells. Moreover, an NF-kappaB binding site i s present in the promoter of the MMP-9 gene and an NF-kappaB-like element i n the promoter of the MMP-1 gene. Methods: We used adenovirus mediated over expression of its inhibitor, I kappaB alpha to investigate the role of NF-k appaB in regulation of MMP-1, -3 and -9 by isolated, cytokine stimulated ra bbit aortic and human saphenous vein VSMC. Results: IL-l alpha potently act ivated NF-kappaB in VSMCs and acted synergistically with growth factors to upregulate expression of MMP-1, -3 and -9. Overexpression of I kappaB alpha , almost completely inhibited expression of MMP-1, -3 and -9 in response to IL-l alpha alone or in combination with bFGF and PDGF. Conclusion: NF-kapp aB is required for cytokine upregulation of MMP-1, -3 and -9 in VSMCs, whic h suggests that NF-kappaB inhibition may promote plaque stabilisation. (C) 2001 Elsevier Science B.V. All rights reserved.