Bone Marrow-Specific Deficiency of Nuclear Receptor Nur77 Enhances Atherosclerosis
Bone Marrow-Specific Deficiency of Nuclear Receptor Nur77 Enhances Atherosclerosis
复制标题
DOI：
10.1161/circresaha.111.260760
复制
发表时间：
2012-02-03
影响因子：
20.1
通讯作者：
de Vries, Carlie J. M.
中科院分区：
文献类型：
--
作者：
Hamers, Anouk A. J.;Vos, Mariska;de Vries, Carlie J. M.
基本原理：核受体Nur 77，也称为NR 4A 1、TR 3或NGFI-B，在巨噬细胞、内皮细胞、T细胞和平滑肌细胞中的人类动脉粥样硬化病变中表达。巨噬细胞Nur 77在动脉粥样硬化中起着重要作用，而Nur 77在病变巨噬细胞中的功能尚未被研究。目的：本研究旨在阐明Nur 77在巨噬细胞中的功能，并评估骨髓特异性Nur 77缺陷对动脉粥样硬化的影响。我们使用来自野生型和Nur 77敲除（Nur 77（-/-））小鼠的骨髓源性巨噬细胞（BMM）研究了Nur 77在巨噬细胞极化中的作用。Nur 77（-/-）BMM表现出M2特异性标志物的表达改变和炎性M1表型，在（未）刺激的Nur 77（-/-）BMM细胞中，白细胞介素-12、IFN γ和SDF-1 α的表达增强，NO合成增加。在未刺激的Nur 77（-/-）BMM中，SDF-1 α表达被Nur 77抑制，并且Nur 77（-/-）BMM的化学吸引活性被SDF-1 α抑制抗体消除。此外，Nur 77（-/-）小鼠显示巯基乙酸盐引起的巨噬细胞和B细胞迁移增强。在低密度脂蛋白受体缺陷（Ldlr（-/-））小鼠中研究了骨髓特异性Nur 77缺陷对动脉粥样硬化的影响。Nur 77（-/-）缺陷骨髓移植的Ldlr（-/-）小鼠比野生型骨髓移植小鼠发生2.1倍大的动脉粥样硬化病变。这些病变含有更多的巨噬细胞、T细胞、平滑肌细胞和更大的坏死核心。SDF-1 α的表达是较高的病变的Nur 77（-/-）-移植小鼠，这可以解释所观察到的恶化的病变formation.Conclusions：总之，在骨髓来源的细胞的核受体Nur 77具有抗炎功能，抑制SDF-1 α的表达和抑制动脉粥样硬化。(Circ Res. 2012;110：428-438）。
Rationale: Nuclear receptor Nur77, also known as NR4A1, TR3, or NGFI-B, is expressed in human atherosclerotic lesions in macrophages, endothelial cells, T cells and smooth muscle cells. Macrophages play a critical role in atherosclerosis and the function of Nur77 in lesion macrophages has not yet been investigated.Objective: This study aims to delineate the function of Nur77 in macrophages and to assess the effect of bone marrow-specific deficiency of Nur77 on atherosclerosis.Methods and Results: We investigated Nur77 in macrophage polarization using bone marrow-derived macrophages (BMM) from wild-type and Nur77-knockout (Nur77(-/-))mice. Nur77(-/-) BMM exhibit changed expression of M2-specific markers and an inflammatory M1-phenotype with enhanced expression of interleukin-12, IFN gamma, and SDF-1 alpha and increased NO synthesis in (non)-stimulated Nur77(-/-) BMM cells. SDF-1 alpha expression in nonstimulated Nur77(-/-) BMM is repressed by Nur77 and the chemoattractive activity of Nur77(-/-) BMM is abolished by SDF-1 alpha inhibiting antibodies. Furthermore, Nur77(-/-) mice show enhanced thioglycollate-elicited migration of macrophages and B cells. The effect of bone marrow-specific deficiency of Nur77 on atherosclerosis was studied in low density lipoprotein receptor-deficient (Ldlr(-/-)) mice. Ldlr(-/-) mice with a Nur77(-/-)-deficient bone marrow transplant developed 2.1-fold larger atherosclerotic lesions than wild-type bone marrow-transplanted mice. These lesions contain more macrophages, T cells, smooth muscle cells and larger necrotic cores. SDF-1 alpha expression is higher in lesions of Nur77(-/-)-transplanted mice, which may explain the observed aggravation of lesion formation.Conclusions: In conclusion, in bone marrow-derived cells the nuclear receptor Nur77 has an anti-inflammatory function, represses SDF-1 alpha expression and inhibits atherosclerosis. (Circ Res. 2012;110:428-438.)