Fibronectin Containing Extra Domain A Induces Plaque Destabilization in the Innominate Artery of Aged Apolipoprotein E-Deficient Mice.
Fibronectin Containing Extra Domain A Induces Plaque Destabilization in the Innominate Artery of Aged Apolipoprotein E-Deficient Mice.
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DOI：
10.1161/atvbaha.117.310345
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发表时间：
2018-03
期刊：
影响因子：
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通讯作者：
Chauhan AK
中科院分区：
文献类型：
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作者：
Doddapattar P;Jain M;Dhanesha N;Lentz SR;Chauhan AK
含有额外结构域A的纤连蛋白（Fibronectin containing extra domain A，Fn-EDA）是Toll样受体4（TLR4）的内源性配体，在人和小鼠动脉粥样硬化病变的细胞外基质（extracellular matrix，ECM）中含量丰富。无论性别如何，Fn-EDA的缺失减少了载脂蛋白缺陷（Apoe −/−）小鼠的早期动脉粥样硬化。然而，Fn-EDA在晚期动脉粥样硬化中的作用仍不清楚。我们确定了Fn-EDA在老年（1岁）Apoe −/−小鼠晚期动脉粥样硬化病变中的作用。在无名动脉中确定斑块组成，已知该斑块不稳定部位模仿脆弱人类斑块的几种组织学特征。雌性Apoe −/−、Fn-EDA −/− Apoe −/−、TLR4 −/− Apoe −/−和Fn-EDA −/− TLR4 −/− Apoe −/−小鼠喂食高脂肪"西方"饮食44周。Fn-EDA −/− Apoe −/−小鼠表现出斑块尺寸减小，其特征在于坏死核心较小，含有丰富的血管平滑肌细胞（VSMC）和胶原蛋白的厚纤维帽，CD68/MMP 9阳性含量减少，MMP切割的ECM聚集蛋白聚糖积聚较少，VSMC和巨噬细胞凋亡减少（与Apoe −/−小鼠相比P <0.05）。总之，这些发现表明，Fn-EDA诱导斑块不稳定。TLR4的缺失减少了Apoe −/−小鼠斑块不稳定的组织学特征，但没有进一步减少Fn-EDA −/− Apoe −/−小鼠斑块不稳定的特征，这表明TLR4可能有助于Fn-EDA诱导的斑块不稳定。Fn-EDA增强了骨髓源性巨噬细胞中TLR 4依赖性MMP 9的表达，表明巨噬细胞TLR 4可能有助于Fn-EDA介导的斑块不稳定性。Fn-EDA在老年Apoe −/−小鼠的已建立病变中诱导斑块不稳定性的组织学特征。晚期动脉粥样硬化病变中Fn-EDA的丰富可能增加斑块不稳定的风险。
Fibronectin containing extra domain A (Fn-EDA) is an endogenous ligand of toll like-receptor 4 (TLR4) and is abundant in the extracellular matrix (ECM) of advanced atherosclerotic lesions in human and mice. Irrespective of gender, deletion of Fn-EDA reduces early atherosclerosis in apolipoprotein-deficient (Apoe−/−) mice. However, the contribution of Fn-EDA in advanced atherosclerosis remains poorly characterized. We determined the contribution of Fn-EDA in advanced atherosclerotic lesions of aged (1-year-old) Apoe−/− mice. Plaque composition was determined in the innominate artery, a plaque instability site that is known to mimic several histological features of vulnerable human plaques. Female Apoe−/−, Fn-EDA−/−Apoe−/−, TLR4−/−Apoe−/− and Fn-EDA−/−TLR4−/−Apoe−/− mice were fed a high-fat “Western” diet for 44 weeks. Fn-EDA−/−Apoe−/− mice exhibited reduced plaque size characterized by smaller necrotic cores, thick fibrous caps containing abundant vascular smooth muscle cells (VSMCs) and collagen, reduced CD68/MMP9-positive content, less accumulation of MMP-cleaved ECM aggrecan, and decreased VSMC and macrophage apoptosis (P<0.05 versus Apoe−/− mice). Together these findings suggest that Fn-EDA induces plaque destabilization. Deletion of TLR4 reduced histological features of plaque instability in Apoe−/− mice but did not further reduce features of plaque destabilization in Fn-EDA−/−Apoe−/− mice, suggesting that TLR4 may contribute to Fn-EDA-induced plaque destabilization. Fn-EDA potentiated TLR4-dependent MMP9 expression in bone marrow-derived macrophages, suggesting that macrophage TLR4 may contribute to Fn-EDA-mediated plaque instability. Fn-EDA induces histological features of plaque instability in established lesions of aged Apoe−/− mice. The abundance of Fn-EDA in advanced atherosclerotic lesions may increase the risk of plaque destabilization.