含额外结构域 A 的纤连蛋白导致载脂蛋白 E 缺陷型高龄小鼠无名动脉斑块不稳定。
Fibronectin Containing Extra Domain A Induces Plaque Destabilization in the Innominate Artery of Aged Apolipoprotein E-Deficient Mice.
机构信息
From the Department of Internal Medicine, The University of Iowa, Iowa City.
出版信息
Arterioscler Thromb Vasc Biol. 2018 Mar;38(3):500-508. doi: 10.1161/ATVBAHA.117.310345. Epub 2018 Jan 11.
OBJECTIVE
Fibronectin containing extra domain A (Fn-EDA) is an endogenous ligand of TLR4 (toll-like receptor 4) and is abundant in the extracellular matrix of advanced atherosclerotic lesions in human and mice. Irrespective of sex, deletion of Fn-EDA reduces early atherosclerosis in apolipoprotein E-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.
APPROACH AND RESULTS
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-EDAApoe, TLR4Apoe, and Fn-EDATLR4Apoe mice were fed a high-fat Western diet for 44 weeks. Fn-EDAApoe mice exhibited reduced plaque size characterized by smaller necrotic cores, thick fibrous caps containing abundant vascular smooth muscle cells and collagen, reduced CD68/MMP9 (matrix metalloproteinase 9)-positive content, less accumulation of MMP-cleaved extracellular matrix aggrecan, and decreased vascular smooth muscle cell and macrophage apoptosis (<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-EDAApoe 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.
CONCLUSIONS
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.
目的
纤维连接蛋白含额外结构域 A（Fn-EDA）是 TLR4（ toll 样受体 4）的内源性配体，在人和小鼠的晚期动脉粥样硬化病变的细胞外基质中含量丰富。无论性别如何，Fn-EDA 的缺失都会减少载脂蛋白 E 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知之甚少。我们确定了 Fn-EDA 在老年（1 岁）Apoe 小鼠的晚期动脉粥样硬化病变中的作用。
方法和结果
在无名动脉（颈总动脉）中确定斑块组成，无名动脉是斑块不稳定的部位，已知其模拟了几种易损人类斑块的组织学特征。雌性 Apoe、Fn-EDAApoe、TLR4Apoe 和 Fn-EDATLR4Apoe 小鼠喂食高脂肪西方饮食 44 周。Fn-EDAApoe 小鼠的斑块体积较小，表现为坏死核心较小，富含血管平滑肌细胞和胶原蛋白的厚纤维帽，CD68/MMP9（基质金属蛋白酶 9）阳性内容物减少，MMP 切割的细胞外基质聚集蛋白聚糖减少，血管平滑肌细胞和巨噬细胞凋亡减少（<0.05 与 Apoe 小鼠相比）。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，但在 Fn-EDAApoe 小鼠中并未进一步减少斑块不稳定的特征，表明 TLR4 可能参与了 Fn-EDA 诱导的斑块不稳定。Fn-EDA 增强了骨髓来源的巨噬细胞中 TLR4 依赖性 MMP9 的表达，表明巨噬细胞 TLR4 可能参与了 Fn-EDA 介导的斑块不稳定。
结论
Fn-EDA 在老年 Apoe 小鼠的已建立病变中诱导斑块不稳定的组织学特征。Fn-EDA 在晚期动脉粥样硬化病变中的丰度可能会增加斑块不稳定的风险。
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