NM23-H2, an estrogen receptor β-associated protein, shows diminished expression with progression of atherosclerosis
NM23-H2, an estrogen receptor β-associated protein, shows diminished expression with progression of atherosclerosis
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DOI：
10.1152/ajpregu.00373.2006
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发表时间：
2007-02-01
影响因子：
2.8
通讯作者：
O'Brien, Edward R.
中科院分区：
文献类型：
--
作者：
Rayner, Katey;Chen, Yong-Xiang;O'Brien, Edward R.
虽然雌激素受体（ER）在雌激素应答中起着重要作用，但受体辅调节因子是信号传导的关键决定因素。虽然卵巢激素对各种正常和病理过程的临床作用是一个活跃的研究领域，但对血管壁等的确切信号作用还不完全清楚。因此，我们试图发现与ER β相关的蛋白质，ER β是动脉损伤后mRNA表达上调的亚型。使用酵母双杂交筛选，我们确定了NM 23-H2，一个多方面的转移抑制候选蛋白，作为ER β相关蛋白。尽管在患有良性内膜增生的年轻受试者（27 +/-6岁，14名男性和6名女性）的动脉中免疫检测到NM 23-H2，但在脂肪条纹/动脉粥样硬化中表达减少，并且在晚期动脉粥样硬化病变中完全不表达。nm 23-H2 mRNA和蛋白在体外培养的血管细胞中均有表达。用17 β-雌二醇和ER β-选择性激动剂二芳基丙腈治疗增加了NM 23-H2的蛋白表达;用ER α-选择性激动剂丙基吡唑三醇未观察到这种作用。雌激素也促进了人冠状动脉平滑肌细胞（SMC）中NM 23-H2蛋白的核定位。体外模拟炎症降低了SMCs中NM 23-H2的表达，其在添加雌激素后恢复并依赖于雌激素受体。总之，我们报告了NM 23-H2与ER β的新关联，并首次显示其在血管细胞中的表达，并证明其表达和定位受雌激素的调节。由于NM 23-H2的丰度随着动脉粥样硬化和炎症的进展而减少，因此这种ER β相关蛋白可能在介导雌激素的血管保护作用中发挥重要作用。
While estrogen receptor ( ER) profile plays an important role in response to estrogens, receptor coregulators act as critical determinants of signaling. Although the clinical effects of ovarian hormones on various normal and pathological processes are an active area of research, the exact signaling effects on, for example, the vessel wall, are incompletely understood. Hence, we sought to discover proteins that associate with ER beta, the isoform that shows upregulated mRNA expression after arterial injury. Using a yeast two-hybrid screen we identified NM23-H2, a multifaceted metastasis suppressor candidate protein, as an ER beta-associated protein. Although NM23-H2 was immunodetected in arteries from young subjects (27 +/- 6 yr, 14 men and 6 women) with benign intimal hyperplasia, expression was diminished in fatty streaks/atheromas and altogether absent in advanced atherosclerotic lesions. Both nm23-H2 mRNA and protein were expressed by vascular cells in vitro. Treatment with 17 beta-estradiol and an ER beta-selective agonist, diarylpropionitrile, increased protein expression of NM23-H2; an effect that was not seen with an ER alpha-selective agonist, propylpyrazole-triol. Estrogen also prompted nuclear localization of NM23-H2 protein in human coronary smooth muscle cells (SMCs). An in vitro mimic of inflammation decreased the expression of NM23-H2 in SMCs, which was restored on addition of estrogen and dependent on the estrogen receptor. In summary, we report the novel association of NM23-H2 with ER beta and show for the first time its expression in vascular cells and demonstrate regulation of its expression and localization by estrogen. In that the abundance of NM23-H2 diminishes with both the advancement of atherosclerosis and inflammation, this ER beta-associated protein may play an important role in mediating the vasculoprotective effects of estrogens.