The orphan nuclear receptor Nur77 inhibits low shear stress-induced carotid artery remodeling in mice.
The orphan nuclear receptor Nur77 inhibits low shear stress-induced carotid artery remodeling in mice.
复制标题
孤儿核受体 Nur77 抑制小鼠低剪切应力诱导的颈动脉重塑
DOI：
10.3892/ijmm.2015.2375
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发表时间：
2015-12
影响因子：
5.4
通讯作者：
He B
中科院分区：
文献类型：
--
作者：
Yu Y;Cai Z;Cui M;Nie P;Sun Z;Sun S;Chu S;Wang X;Hu L;Yi J;Shen L;He B
切应力，特别是低切应力和振荡切应力，在血管重构相关的心血管疾病中起着关键的病理生理作用。越来越多的证据表明，孤儿核受体Nur77 [也称为TR3或核受体亚家族4，A组，成员1（NR4A1）]在患病的人血管组织中表达，并在血管生理学和病理学中起重要作用。在本研究中，我们使用了小鼠模型的流量依赖性重塑部分结扎左颈总动脉（LCCA），以确定确切的作用，Nur77在血管重塑低切应力诱导。在血管重塑后，Nur77在结扎的颈动脉中的新生内膜血管平滑肌细胞（VSMCs）中高度表达。血小板源性生长因子（PDGF）刺激后，体内重塑动脉和体外原代大鼠VSMCs中活性氧（ROS）水平升高。进一步的体外实验显示，在用PDGF和H2O2刺激后，VSMC中Nur77的表达迅速增加，而用N-乙酰半胱氨酸（NAC，ROS清除剂）处理逆转了H2O2诱导的Nur77蛋白水平的增加。此外，Nur77过表达显著抑制PDGF诱导的VSMCs增殖和迁移。最后，为了确定Nur77在低剪切应力诱导的血管重塑中的体内作用，对野生型（WT）和Nur77缺陷型小鼠进行LCCA的部分结扎。手术后四周，在Nur77缺陷小鼠的LCCA中，与WT小鼠相比，注意到内膜-中层面积和颈动脉内膜-中层厚度显著增加，以及更严重的弹性蛋白破坏和胶原沉积。免疫荧光染色显示Nur77缺陷小鼠的VSMC增殖[通过增殖细胞核抗原（PCNA）的表达确定]和基质金属蛋白酶9（MMP-9）的产生增加。两组间内膜凋亡细胞数量无差异。综上所述，我们的结果表明，Nur77可能是氧化应激的传感器和低切应力诱导的血管重构的抑制剂。因此，Nur77及其下游细胞信号可能是抑制血管重塑的潜在治疗靶点。
Shear stress, particularly low and oscillatory shear stress, plays a critical pathophysiological role in vascular remodeling-related cardiovascular diseases. Growing evidence suggests that the orphan nuclear receptor Nur77 [also known as TR3 or nuclear receptor subfamily 4, group A, member 1 (NR4A1)] is expressed in diseased human vascular tissue and plays an important role in vascular physiology and pathology. In the present study, we used a mouse model of flow-dependent remodeling by partial ligation of the left common carotid artery (LCCA) to define the exact role of Nur77 in vascular remodeling induced by low shear stress. Following vascular remodeling, Nur77 was highly expressed in neointimal vascular smooth muscle cells (VSMCs) in the ligated carotid arteries. The reactive oxygen species (ROS) levels were elevated in the remodeled arteries in vivo and in primary rat VSMCs in vitro following stimulation with platelet-derived growth factor (PDGF). Further in vitro experiments revealed that Nur77 expression was rapidly increased in the VSMCs following stimulation with PDGF and H2O2, whereas treatment with N-acetyl cysteine (NAC, a ROS scavenger) reversed the increase in the protein level of Nur77 induced by H2O2. Moreover, Nur77 overexpression markedly inhibited the proliferation and migration of VSMCs, induced by PDGF. Finally, to determine the in vivo role of Nur77 in low shear stress-induced vascular remodeling, wild-type (WT) and Nur77-deficient mice were subjected to partial ligation of the LCCA. Four weeks following surgery, in the LCCAs of the Nur77-deficient mice, a significant increase in the intima-media area and carotid intima-media thickness was noted, as well as more severe elastin disruption and collagen deposition compared to the WT mice. Immunofluorescence staining revealed an increase in VSMC proliferation [determined by the expression of proliferating cell nuclear antigen (PCNA)] and matrix metalloproteinase 9 (MMP-9) production in the Nur77-deficient mice. There was no difference in the number of intimal apoptotic cells between the groups. Taken together, our results indicate that Nur77 may be a sensor of oxidative stress and an inhibitor of vascular remodeling induced by low shear stress. Nur77, as well as its downstream cell signals, may thus be a potential therapeutic target for the suppression of vascular remodeling.