Orphan Nuclear Receptor Nur77 Inhibits Angiotensin II-Induced Vascular Remodeling via Downregulation of β-Catenin
Orphan Nuclear Receptor Nur77 Inhibits Angiotensin II-Induced Vascular Remodeling via Downregulation of β-Catenin
复制标题
孤儿核受体 Nur77 通过下调 β-Catenin 抑制血管紧张素 II 诱导的血管重塑。
DOI：
10.1161/hypertensionaha.115.06114
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发表时间：
2016-01-01
期刊：
影响因子：
8.3
通讯作者：
He, Ben
中科院分区：
文献类型：
--
作者：
Cui, Mingli;Cai, Zhaohua;He, Ben
血管紧张素II （Ang II）是肾素-血管紧张素系统的主要效应肽。Ang II在许多心血管疾病（如高血压、动脉粥样硬化、再狭窄和动脉瘤）中参与血管重塑。孤儿核受体Nur77在血管细胞的功能调控中具有重要作用。本研究的目的是确定Nur77在Ang ii诱导的血管重构中的具体作用。在小鼠胸主动脉内侧血管平滑肌细胞（VSMCs）中，通过皮下渗透微型泵连续注入Ang II 2周，Nur77表达升高。细胞研究表明，Ang II通过MAPK/PKA-CREB信号通路上调Nur77的表达。与野生型VSMCs相比，从Nur77（-/-）小鼠分离的VSMCs中，Ang ii诱导的增殖、迁移和表型转换显著增强。与在VSMCs中的作用一致，我们发现，与野生型小鼠相比，Nur77（-/-）小鼠在外源性Ang II给药2周后，主动脉内侧面积和管腔直径增加，弹性蛋白破坏和胶原沉积更严重，VSMC增殖和基质金属蛋白酶生成增加，VSMC特异性基因SM-22和-actin表达降低。进一步的实验结果表明，Nur77通过促进-catenin降解和抑制其转录活性来抑制Ang ii诱导的-catenin信号通路的激活。我们的研究结果表明，Nur77是Ang ii诱导的VSMC增殖、迁移和表型转换的关键负调控因子，通过下调-catenin活性。Nur77可能减少许多心血管疾病中Ang ii诱导的血管重构。
Angiotensin II (Ang II) is the predominant effector peptide of the renin-angiotensin system. Ang II contributes to vascular remodeling in many cardiovascular diseases (eg, hypertension, atherosclerosis, restenosis, and aneurysm). Orphan nuclear receptor Nur77 has a crucial role in the functional regulation of vascular cells. The objective of this study was to define the specific role of Nur77 in Ang II-induced vascular remodeling. Nur77 expression was initially found to be elevated in medial vascular smooth muscle cells (VSMCs) of thoracic aortas from mice continuously infused with Ang II for 2 weeks using a subcutaneous osmotic minipump. Cellular studies revealed that Nur77 expression was upregulated by Ang II via the MAPK/PKA-CREB signaling pathway. Ang II-induced proliferation, migration, and phenotypic switching were significantly enhanced in VSMCs isolated from Nur77(-/-) mice compared with wild-type VSMCs. Consistent with the role in VSMCs, we found that compared with wild-type mice, Nur77(-/-) mice had elevated aortic medial areas and luminal diameters, more severe elastin disruption and collagen deposition, increased VSMC proliferation and matrix metalloproteinase production, and decreased VSMC-specific genes SM-22 and -actin expression, after 2 weeks of exogenous Ang II administration. The results of additional experiments suggested that Nur77 suppressed Ang II-induced -catenin signaling pathway activation by promoting -catenin degradation and inhibiting its transcriptional activity. Our findings indicated that Nur77 is a critical negative regulator of Ang II-induced VSMC proliferation, migration, and phenotypic switching via the downregulation of -catenin activity. Nur77 may reduce Ang II-induced vascular remodeling involved in many cardiovascular diseases.