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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:765.)
© 2002 American Heart Association, Inc.

Vascular Biology

Role of Nuclear Factor-B Activation in Metalloproteinase-1, -3, and -9 Secretion by Human Macrophages In Vitro and Rabbit Foam Cells Produced In Vivo

Alexander J. Chase; Mark Bond; Martin F. Crook; Andrew C. Newby

From the University of Bristol, Bristol Heart Institute, Bristol, UK.

Correspondence to Prof Andrew Newby, Bristol Heart Institute, Bristol Royal Infirmary, Bristol BS2 8HW, UK. E-mail A.Newby@ bris.ac.uk

Metalloproteinase secretion by macrophages is believed to play a key role in the matrix degradation that underlies atherosclerotic plaque instability and aneurysm formation. We studied the hypothesis that nuclear factor-B (NF-B), a transcription factor, is necessary for metalloproteinase secretion and, hence, is a target for pharmacological intervention. Adenovirus-mediated gene transfer of the inhibitory NF-B subunit, I- B, was achieved into human monocyte-derived macrophages in vitro and into foam cells produced in vivo in cholesterol-fed rabbits. Human macrophages and rabbit foam cells secreted matrix-degrading metalloproteinase (MMP)-9 without further stimulation, and this was not inhibited by I-B (11±16% and 8±10%, respectively; P> 0.05). MMP-1 secretion from human macrophages increased in response to recombinant human CD40 ligand and was inhibited 92±5% by I-B (n=3, P<0.05). Rabbit foam cells secreted MMP-1 and -3 without further stimulation, and this was inhibited 83±12% and 69±11%, respectively, by I-B (n=6 or 7, P<0.001). I-B did not significantly affect the expression or activity of tissue inhibitor of metalloproteinases-1 or -2. Overexpression of I-B inhibited collagenolytic and ß-caseinolytic activity by 42±2% and 41±7%, respectively (n=3, P<0.05). Secretion of MMP-1 and MMP-3 from macrophages stimulated in vitro or in vivo depends on the activation of NF-B. Because the inhibition of NF-B reduces proteolytic activity, it appears to be an attractive pharmacological target in unstable atheromas.

Key Words: macrophages • foam cells • metalloproteinases • nuclear factor-B

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