Published online before print March 14, 2002, doi: 10.1161/01.ATV.0000015078.09208.92
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© 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
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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