Induction of Nur77 by hyperoside inhibits vascular smooth muscle cell proliferation and neointimal formation.
Induction of Nur77 by hyperoside inhibits vascular smooth muscle cell proliferation and neointimal formation.
复制标题
金丝桃苷诱导 Nur77 抑制血管平滑肌细胞增殖和新内膜形成。
DOI：
10.1016/j.bcp.2014.09.021
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发表时间：
2014-12-15
影响因子：
5.8
通讯作者：
Sun J
中科院分区：
文献类型：
--
作者：
Huo Y;Yi B;Chen M;Wang N;Chen P;Guo C;Sun J
Nur77 是一种孤儿核受体，属于核受体 4A (NR4A) 亚家族，与细胞凋亡、增殖、炎症和代谢等多种生物事件有关。 Nur77的激活最近被证明有利于心血管和代谢疾病的治疗。本研究的目的是鉴定新型天然 Nur77 激活剂并研究其在预防血管疾病中的作用。通过使用定量 RT-PCR 测量 Nur77 表达，我们筛选了从中草药中提取的具有有益心血管作用的活性成分。金丝桃苷（槲皮素 3-D-半乳糖苷）被确定为诱导 Nur77 表达并激活其在血管平滑肌细胞 (VSMC) 中转录活性的有效激活剂之一。我们证明金丝桃苷以时间和剂量依赖性方式显着增加大鼠 VSMC 中 Nur77 的表达，EC50 为~0.83μM。从机制上讲，我们发现金丝桃苷显着增加 ERK1/2 MAP 激酶及其下游靶 cAMP 反应元件结合蛋白 (CREB) 的磷酸化，这两者都有助于金丝桃苷诱导大鼠 VSMC 中的 Nur77 表达。此外，通过激活 Nur77 受体，金丝桃苷显着抑制体外血管平滑肌细胞增殖和体内颈动脉结扎诱导的新内膜形成。这些发现表明金丝桃苷是 Nur77 受体的有效天然激活剂，可潜在用于预防和治疗闭塞性血管疾病。
Nur77 is an orphan nuclear receptor that belongs to the nuclear receptor 4A (NR4A) subfamily, which has been implicated in a variety of biological events, such as cell apoptosis, proliferation, inflammation, and metabolism. Activation of Nur77 has recently been shown to be beneficial for the treatment of cardiovascular and metabolic diseases. The purpose of this study is to identify novel natural Nur77 activators and investigate their roles in preventing vascular diseases. By measuring Nur77 expression using quantitative RT-PCR, we screened active ingredients extracted from Chinese herb medicines with beneficial cardiovascular effects. Hyperoside (quercetin 3-D-galactoside) was identified as one of the potent activators for inducing Nur77 expression and activating its transcriptional activity in vascular smooth muscle cells (VSMCs). We demonstrated that hyperoside, in a time and dose dependent manner, markedly increased the expression of Nur77 in rat VSMCs, with an EC50 of ∼0.83μM. Mechanistically, we found that hyperoside significantly increased the phosphorylation of ERK1/2 MAP kinase and its downstream target cAMP response element-binding protein (CREB), both of which contributed to the hyperoside-induced Nur77 expression in rat VSMCs. Moreover, through activation of Nur77 receptor, hyperoside markedly inhibited both vascular smooth muscle cell proliferation in vitro and the carotid artery ligation–induced neointimal formation in vivo. These findings demonstrate that hyperoside is a potent natural activator of Nur77 receptor, which can be potentially used for prevention and treatment of occlusive vascular diseases.
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