Cardiovascular Research Institute, MedStar Health Research Institute, 108 Irving Street, NW Washington, DC 20010, USA.
Dis Model Mech. 2013 Mar;6(2):323-31. doi: 10.1242/dmm.009977. Epub 2013 Jan 11.
The primary purpose of this investigation was to determine whether ApoE(-/-) mice, when subjected to chronic stress, exhibit lesions characteristic of human vulnerable plaque and, if so, to determine the time course of such changes. We found that the lesions were remarkably similar to human vulnerable plaque, and that the time course of lesion progression raised interesting insights into the process of plaque development. Lard-fed mixed-background ApoE(-/-) mice exposed to chronic stress develop lesions with large necrotic core, thin fibrous cap and a high degree of inflammation. Neovascularization and intraplaque hemorrhage are observed in over 80% of stressed animals at 20 weeks of age. Previously described models report a prevalence of only 13% for neovascularization observed at a much later time point, between 36 and 60 weeks of age. Thus, our new stress-induced model of advanced atherosclerotic plaque provides an improvement over what is currently available. This model offers a tool to further investigate progression of plaque phenotype to a more vulnerable phenotype in humans. Our findings also suggest a possible use of this stress-induced model to determine whether therapeutic interventions have effects not only on plaque burden, but also, and importantly, on plaque vulnerability.
本研究的主要目的是确定慢性应激是否会使载脂蛋白 E 基因敲除（ApoE(-/-)）小鼠出现与人易损斑块特征一致的病变，如果是这样，确定这种变化的时程。我们发现病变与人类易损斑块非常相似，病变进展的时程为斑块发展过程提供了有趣的见解。用富含脂肪的混合背景 ApoE(-/-) 小鼠进行慢性应激可导致出现大的坏死核心、薄的纤维帽和高度炎症的病变。在 20 周龄时，超过 80%的应激动物观察到新生血管形成和斑块内出血。先前描述的模型报告称，在 36 至 60 周龄之间的更晚时间点观察到新生血管形成的发生率仅为 13%。因此，我们新的应激诱导的晚期动脉粥样硬化斑块模型优于目前可用的模型。该模型提供了一种工具，可以进一步研究斑块表型向人类更易损表型的进展。我们的研究结果还表明，这种应激诱导模型可能被用于确定治疗干预不仅对斑块负担，而且对斑块易损性是否有影响。
