EXPRESSION OF A CONSTITUTIVE NF-KAPPA-B-LIKE ACTIVITY IS ESSENTIAL FOR PROLIFERATION OF CULTURED BOVINE VASCULAR SMOOTH-MUSCLE CELLS
EXPRESSION OF A CONSTITUTIVE NF-KAPPA-B-LIKE ACTIVITY IS ESSENTIAL FOR PROLIFERATION OF CULTURED BOVINE VASCULAR SMOOTH-MUSCLE CELLS
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DOI：
10.1172/jci118313
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发表时间：
1995-11-01
影响因子：
15.9
通讯作者：
SONENSHEIN, GE
中科院分区：
文献类型：
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作者：
BELLAS, RE;LEE, JS;SONENSHEIN, GE
我们最近发现牛和人血管平滑肌细胞（SMC）表达新的组成型核因子-κ B（NF-κ B）/Rel样活性（Lawrence，R.，L- J. Chang，U. Siebenlist，P. Bressler，and G. E.索南辛1994. 269：28913-28918），在此称为SMC-Rel.由于人血管平滑肌细胞的巨细胞病毒（CMV）感染与血管成形术后再狭窄过程中平滑肌细胞的异常增殖有关，我们检测了NF-κ B/Rel活性在CMV立即早期（即）启动子反式激活中的作用。基础CMV ie启动子与其NF-κ B元件的三个野生型拷贝相连，但不是突变型拷贝，在牛主动脉SMC中具有活性。临床上用于降低NF-κ B/Rel活性的抗氧化剂N-乙酰半胱氨酸（NAC）或戊乙茶碱（PTX）抑制NF-κ B驱动的启动子反式激活和SMC-Rel结合活性。观察到用NAC或PTX处理以剂量依赖性方式减缓SMC的生长。显微注射纯化的I κ B-α（一种天然存在的NF-κ B/Rel活性特异性抑制剂）或携带野生型但非NF-κ B元件非结合突变体的双链寡核苷酸选择性抑制SMC增殖。因此，组成性NF-κ B/Rel活性似乎是血管平滑肌细胞增殖所必需的，并可能成为再狭窄治疗干预的新靶点。
We have recently discovered bovine and human vascular smooth muscle cells (SMCs) express a novel constitutive Nuclear Factor-kappa B (NF-kappa B)/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-kappa B/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-kappa B element was active in bovine aortic SMCs. The anti-oxidants N-acetyl cysteine (NAC) or pentoxifylline (PTX), which are used clinically to reduce NF-kappa B/Rel activity, inhibited NF-kappa B 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 I kappa B-alpha, a naturally occurring specific inhibitor of NF-kappa B/Rel activity, or double-stranded oligonucleotides harboring wild type, but not non-binding mutants of NF-kappa B elements selectively inhibited SMC proliferation. Thus constitutive NF-kappa B/Rel activity appears essential for proliferation of vascular SMCs and might be a novel target for therapeutic intervention for restenosis.