We have recently discovered bovine and human vascular smooth muscle cells (SMCs) express a novel constitutive Nuclear Factor-cB (NF-cB)/Rel-like activity (Lawrence, R., L.-J. Chang, U. Siebenlist, P. Bressler, and G. E. Sonenshein. 1994. J. Biol Chem. 269:28913-28918), here termed SMC-Rel. Since cytomegalovirus (CMV) infection of human vascular SMCs has been implicated in aberrant SMC proliferation during post-angioplasty restenosis, we tested the role of NF-icB/Rel activity in transactivation of the CMV immediate early (ie) promoter. The basal CMV ie promoter linked to three wild-type, but not mutant, copies of its NF-#cB element was active in bovine aortic SMCs.The anti-oxidants N-acetyl cysteine (NAC) or pentoxifylline (PTX), which are used clinically to reduce NF-icB/Rel activity, inhibited NF-icB driven promoter transactivation, and SMC-Rel binding activity. Treatment with either NAC or PTX was observed to slow the growth of the SMCs in a dose dependent fashion. Microinjection of either purified bcB-a, a naturally occurring specific inhibitor of NF-icB/Rel activity, or double-stranded oligonucleotides harboring wild type, but not non-binding mutants of NF-#cB elements selectively inhibited SMC proliferation. Thus constitutive NFKcB/Rel activity appears essential for proliferation of vascular SMCs and might be a novel target for therapeutic intervention for restenosis. (J. Clin.
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