Regulation of vascular smooth muscle cell proliferation role of NF-κΒ revisited
Regulation of vascular smooth muscle cell proliferation role of NF-κΒ revisited
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DOI：
10.1161/01.res.0000166924.31219.49
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发表时间：
2005-05-13
影响因子：
20.1
通讯作者：
Scheidereit, C
中科院分区：
文献类型：
--
作者：
Mehrhof, FB;Schmidt-Ullrich, R;Scheidereit, C
转录因子NF-κ B调节许多细胞类型中的细胞周期进程和增殖。一个重要的未解决的问题是NF-κ B B在血管平滑肌细胞（VSMC）增殖中的潜在作用，作为血管疾病发展的基础。为了研究NF-κ B对有丝分裂原诱导的VSMC增殖的贡献，使用表达NF-κ B超阻遏物I κ B α δ N（c（I κ B α δ N））的敲入小鼠模型。比较野生型和I κ B α Delta N表达的VSMCs，我们发现血小板衍生生长因子-BB（PDGF-BB）或血清促有丝分裂刺激后增殖率没有差异。与此一致，在来源于表达NF-κ B依赖性lacZ报告基因（c（（Igk）3conalacZ））的转基因小鼠的VSMC中未观察到NF-κ B活化。我们进一步表明，经典的促有丝分裂信号通路（即丝裂原活化蛋白激酶[MAPK]和磷脂酰肌醇-3-OH-激酶[PI 3 K]通路）控制VSMC增殖，但独立于NF-κ B B活化。与VSMC相反，来自I κ B α Delta N表达小鼠的小鼠胚胎成纤维细胞（MEF）在促有丝分裂刺激后显示出显著受损的增殖率。这反映在来自（c（I κ B alpha Delta N））小鼠的血清刺激的MEFs中强烈受损的细胞周期蛋白D1表达。这些结果暗示NF-κ B B在动脉粥样硬化发展中的基本致病功能涉及VSMC的凋亡和炎症信号而不是增殖。它们进一步提供了在控制细胞增殖中NF-κ B的细胞类型限制性需求的遗传证据。
The transcription factor NF-kappa B regulates cell cycle progression and proliferation in a number of cell types. An important unresolved issue is the potential role of NF-kappa B in the proliferation of vascular smooth muscle cells (VSMCs) as a basis for the development of vascular disease. To investigate the contribution of NF-kappa B to mitogen-induced proliferation of VSMCs, a knock-in mouse model expressing the NF-kappa B superrepressor I kappa B alpha Delta N (c(I kappa B alpha Delta N)) was used. Comparing wild-type and I kappa B alpha Delta N-expressing VSMCs, we found that proliferation rates did not differ after mitogenic stimulation by platelet-derived growth-factor-BB (PDGF-BB) or serum. In line with this, NF-kappa B activation was not observed in VSMCs derived from transgenic mice expressing an NF-kappa B-dependent lacZ reporter (c((Igk)3conalacZ)). We further show, that classical mitogenic signaling pathways (namely mitogen-activated protein kinase [MAPK] and the phosphatidyl-inositol-3-OH-kinase [PI3K] pathways) control VSMC proliferation, but independently of NF-kappa B activation. In contrast to VSMCs, mouse embryonic fibroblasts (MEFs) derived from I kappa B alpha Delta N-expressing mice showed significantly impaired proliferation rates after mitogenic stimulation. This was reflected by strongly impaired cyclin D1 expression in serum-stimulated MEFs derived from (c(I kappa B alpha Delta N)) mice. These results implicate that essential pathogenetic functions of NF-kappa B in the development of atherosclerosis involve apoptotic and inflammatory signaling of VSMCs rather than proliferation. They further provide genetic evidence for a cell-type restricted requirement of NF-kappa B in the control of cellular proliferation.