Insulin-Like Growth Factor-1 Receptor Deficiency in Macrophages Accelerates Atherosclerosis and Induces an Unstable Plaque Phenotype in Apolipoprotein E-Deficient Mice.
Insulin-Like Growth Factor-1 Receptor Deficiency in Macrophages Accelerates Atherosclerosis and Induces an Unstable Plaque Phenotype in Apolipoprotein E-Deficient Mice.
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DOI：
10.1161/circulationaha.116.021805
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发表时间：
2016-06-07
期刊：
影响因子：
37.8
通讯作者：
Delafontaine P
中科院分区：
文献类型：
--
作者：
Higashi Y;Sukhanov S;Shai SY;Danchuk S;Tang R;Snarski P;Li Z;Lobelle-Rich P;Wang M;Wang D;Yu H;Korthuis R;Delafontaine P
我们之前已经证明，全身输注胰岛素样生长因子-1 (IGF-1) 可发挥抗炎和抗氧化作用，并减轻载脂蛋白 E (Apoe) 缺陷小鼠的动脉粥样硬化负担。单核细胞/巨噬细胞表达高水平的 IGF-1 受体 (IGF1R)，在动脉粥样硬化形成中发挥关键作用，但 IGF-1 对其功能的潜在影响尚不清楚。为了确定 IGF-1 减少动脉粥样硬化的机制并探索单核细胞/巨噬细胞的潜在参与，我们在 Apoe−/− 背景下创建了单核细胞/巨噬细胞特异性 IGF1R 敲除 (MΦ-IGF1R-KO) 小鼠。我们评估了动脉粥样硬化负荷、斑块稳定性特征以及动脉粥样硬化病变的单核细胞募集。在培养物中研究了 IGF1R 缺陷型巨噬细胞的表型变化。通过主动脉面和主动脉根部横截面的油红-O染色评估，MΦ-IGF1R-KO显着增加了动脉粥样硬化病变的形成，并将斑块组成改变为不太稳定的表型，其特征是巨噬细胞增加和α-平滑肌肌动蛋白阳性细胞群减少、纤维帽变薄和胶原含量减少。 MΦ-IGF1R-KO 小鼠的头臂动脉病变具有暗示斑块易损性的组织学特征。从 MΦ-IGF1R-KO 小鼠中分离的巨噬细胞在 IFNγ 和氧化 LDL 刺激下表现出增强的促炎反应，并且抗氧化基因表达水平升高。此外，IGF1R缺陷的巨噬细胞ABCA1和ABCG1的表达降低，脂质流出减少。我们的数据表明，巨噬细胞 IGF1R 信号传导抑制病变中巨噬细胞和泡沫细胞的积累，并减少斑块的脆弱性，从而提供了 IGF-1 发挥抗动脉粥样硬化作用的新机制。
We have previously shown that systemic infusion of insulin-like growth factor-1 (IGF-1) exerts anti-inflammatory and anti-oxidant effects and reduces atherosclerotic burden in apolipoprotein E (Apoe) deficient mice. Monocytes/macrophages express high levels of IGF-1 receptor (IGF1R) and play a pivotal role in atherogenesis but the potential effects of IGF-1 on their function are unknown. To determine mechanisms whereby IGF-1 reduces atherosclerosis and to explore the potential involvement of monocytes/macrophages, we created monocyte/ macrophage specific IGF1R knockout (MΦ-IGF1R-KO) mice on Apoe−/− background. We assessed atherosclerotic burden, plaque features of stability, and monocyte recruitment to atherosclerotic lesions. Phenotypic changes of IGF1R-deficient macrophages were investigated in culture. MΦ-IGF1R-KO significantly increased atherosclerotic lesion formation, as assessed by Oil-red-O staining of en face aortae and aortic root cross-sections, and changed plaque composition to a less stable phenotype, characterized by increased macrophage and decreased α-smooth muscle actin-positive cell population, fibrous cap thinning, and decreased collagen content. Brachiocephalic artery lesions of MΦ-IGF1R-KO mice had histological features implying plaque vulnerability. Macrophages isolated from MΦ-IGF1R-KO mice showed enhanced proinflammatory responses upon stimulation by IFNγ and oxidized LDL and elevated antioxidant gene expression levels. Moreover, IGF1R deficient macrophages had decreased expression of ABCA1 and ABCG1 and reduced lipid efflux. Our data indicate that macrophage IGF1R signaling suppresses macrophage and foam cell accumulation in lesions and reduces plaque vulnerability, providing a novel mechanism whereby IGF-1 exerts anti-atherogenic effects.