The LDLR deficient mouse as a model for aortic calcification and quantification by micro-computed tomography
The LDLR deficient mouse as a model for aortic calcification and quantification by micro-computed tomography
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DOI：
10.1016/j.atherosclerosis.2011.08.035
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发表时间：
2011-12-01
期刊：
影响因子：
5.3
通讯作者：
Genest, Jacques
中科院分区：
文献类型：
--
作者：
Awan, Zuhier;Denis, Maxime;Genest, Jacques
目的：低密度脂蛋白受体(LDLR)基因突变导致的家族性高胆固醇血症(FH)患者会出现主动脉过早钙化，这种效应是年龄和基因剂量依赖性的，并且在以后的生活中胆固醇水平不受影响。为了更好地理解这一过程，我们研究了一个小鼠模型。方法：我们比较了6个月、12个月和18个月时喂食Ldlr(-/-)的小鼠与6个月时喂食西方饮食(WD)的小鼠。此外，我们将对照组与LDLR(-/-)小鼠和过表达PCSK9的转基因小鼠TG(PCSK9)进行了比较，PCSK9促进了LDLR的降解。主动脉灌流固定，石蜡包埋，切片茜素红染色。结果：LDLR(-/-)小鼠在升主动脉、横主动脉和颈部血管出现钙化，其分布与人类相似。钙化在喂食食物的18个月大的Ldlr(-/-)小鼠和喂食WD的6个月大的Ldlr(-/-)小鼠中最为明显。有趣的是，喂食WD的TG(PCSK9)小鼠也出现了主动脉钙化。组织学证实钙化以内膜下为主。LRP5和WNT在LDLR(-/-)和TG(PCSK9)模型中均有显著表达，但在年龄匹配的对照组中无明显表达。结论：两种模型均可形成年龄和饮食依赖性的主动脉钙化。LRP5/Wnt通路的异常调节可能在钙化过程中起一定作用。使用这种微型CT成像技术进一步分析这些主动脉钙化模型可能会更好地了解FH和动脉钙化之间的联系。(C)2011爱思唯尔爱尔兰有限公司。保留所有权利。
Objective: Patients with familial hypercholesterolemia (FH) due mutations in the low-density lipoprotein receptor (LDLR) suffer premature aortic calcification, an effect that is age-and gene dosage-dependent and cholesterol level independent later in life. To better understand this process, we examined a murine model.Methods: We compared chow fed Ldlr(-/-) mice to controls at 6, 12 and 18 months and on a Western diet (WD) at 6 months. Additionally, we compared controls to Ldlr(-/-) mice and transgenic mice Tg(Pcsk9) overexpressing PCSK9, which promotes LDLR degradation. Aortas were perfused-fixed, embedded in paraffin, and sections were stained with alizarin red. Micro-computerized tomography (micro-CT) was used to quantify vascular calcification.Results: Ldlr(-/-) mice develop calcification in the ascending, transverse aorta and neck vessels with a distribution similar to that of human. Calcification was most prominent in 18-month-old Ldlr(-/-) mice fed a chow diet and in 6-month-old Ldlr(-/-) mice fed a WD. Interestingly, Tg(Pcsk9) mice fed a WD develop aortic calcifications as well. Histology confirmed that the calcification were predominantly sub-intimal. Marked expression of LRP5 and WNT was observed in the Ldlr(-/-) and Tg(Pcsk9) models, but not in age-matched controls.Conclusions: The two mouse models develop aortic calcification in an age-and diet-dependent manner. Abnormal regulation of the LRP5/Wnt pathway may play a role in the calcification process. Further analysis of these aortic calcification models using this micro-CT imaging technique may provide a better understanding of the link between FH and arterial calcification. (C) 2011 Elsevier Ireland Ltd. All rights reserved.