Neuron-derived orphan receptor-1 (NOR-1) modulates vascular smooth muscle cell proliferation
Neuron-derived orphan receptor-1 (NOR-1) modulates vascular smooth muscle cell proliferation
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DOI：
10.1161/01.es.0000050921.53008.47
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发表时间：
2003-01-10
影响因子：
20.1
通讯作者：
Badimon, L
中科院分区：
文献类型：
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作者：
Martínez-González, J;Rius, J;Badimon, L
血管平滑肌细胞（VSMCs）的迁移和增殖在心血管疾病的病理生理过程中起着关键作用。然而，调控VSMC活化的转录因子还没有完全确定。通过mRNA差异显示方法，我们已经确定了神经元源性孤儿受体-1（NOR-1），核受体NGFI-B亚家族内的转录因子，作为VSMC中的立即早期基因。从血清诱导的猪VSMC中鉴定并克隆了两种NOR-1亚型（α和β），它们与人类亚型具有高度同源性。北方印迹分析显示，生长因子（血清，血小板衍生生长因子-BB，和表皮生长因子）和α-凝血酶，但不是由细胞因子在猪和人冠状动脉SMC的NOR-1的强烈和短暂的（1至6小时）上调。NOR-1上调通过G蛋白偶联受体和酪氨酸激酶受体进行，并涉及Ca 2+动员、蛋白激酶C活化和促分裂原活化蛋白激酶途径。转染试验表明，这种诱导与NOR-1启动子中存在的cAMP反应元件密切相关。人冠状动脉粥样硬化病变过表达NOR-1，球囊血管成形术瞬时诱导NOR-1在猪冠状动脉中的模式类似于在培养的VSMC中观察到的模式。针对NOR-1的反义寡核苷酸与针对原癌基因c-fos的反义寡核苷酸一样有效地抑制人冠状动脉SMC增殖（减少从头DNA合成、细胞周期进展和VSMC伤口修复）。这些结果表明，NOR-1调节VSMC增殖，并建议，这种转录因子可能在自发和加速动脉粥样硬化中发挥作用。
Vascular smooth muscle cells (VSMCs) migration and proliferation play a key role in the pathophysiology of cardiovascular disease. However, the transcription factors that regulate VSMC activation are not completely characterized. By a mRNA-differential display approach, we have identified neuron-derived orphan receptor-1 (NOR-1), a transcription factor within the NGFI-B subfamily of nuclear receptors, as a immediate-early gene in VSMCs. Two NOR-1 isoforms (alpha and beta) were identified and cloned from serum-induced porcine VSMC that shared high homology with the human isoforms. Northern blot analysis revealed a strong and transient (I to 6 hours) upregulation of NOR-1 in both porcine and human coronary SMCs by growth factors (serum, platelet-derived growth factor-BB, and epidermal growth factor) and alpha-thrombin but not by cytokines. NOR-1 upregulation is processed through G protein-coupled receptors and tyrosine kinase receptors, and involves Ca2+ mobilization, protein kinase C activation, and the mitogen-activated protein kinase pathway. This induction was closely dependent of the cAMP response elements present in NOR-1 promoter as transfection assays indicate. Human coronary atherosclerotic lesions overexpress NOR-1, and balloon angioplasty transiently induces NOR-1 in porcine coronary arteries with a pattern similar to that observed in VSMCs in culture. Antisense oligonucleotides against NOR-1 inhibited human coronary SMC proliferation (reduced de novo DNA synthesis, cell cycle progression, and VSMC wound repair) as efficiently as antisense against the protooncogene c-fos. These results show that NOR-1 modulates VSMC proliferation, and suggest that this transcription factor may play a role in both spontaneous and accelerated atherosclerosis.