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

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Abstract
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-kappaB, which regulates numerous inflammatory genes, and is activated in plaque smooth muscle cells. Moreover, an NF-kappaB binding site is present in the promoter of the MMP-9 gene and an NF-kappaB-like element in the promoter of the MMP-1 gene. We used adenovirus mediated overexpression of its inhibitor, I kappaBalpha to investigate the role of NF-kappaB in regulation of MMP-1, -3 and -9 by isolated, cytokine stimulated rabbit aortic and human saphenous vein VSMC. IL-1alpha potently activated NF-kappa B in VSMCs and acted synergistically with growth factors to upregulate expression of MMP-1, -3 and -9. Overexpression of I kappaBalpha, almost completely inhibited expression of MMP-1, -3 and -9 in response to IL-1alpha alone or in combination with bFGF and PDGF. NF-kappaB is required for cytokine upregulation of MMP-1, -3 and -9 in VSMCs, which suggests that NF-kappaB inhibition may promote plaque stabilisation.

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