The AAV-PCSK9 murine model of atherosclerosis and metabolic dysfunction.
The AAV-PCSK9 murine model of atherosclerosis and metabolic dysfunction.
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DOI：
10.1093/ehjopen/oeac028
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发表时间：
2022-05
期刊：
影响因子：
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通讯作者：
Galkina, Elena V
中科院分区：
文献类型：
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作者：
Keeter, William Coles;Carter, Nigeste M;Nadler, Jerry L;Galkina, Elena V
研究动脉粥样硬化和相关代谢综合征需要基因修饰的小鼠模型。在C57 BL/6小鼠中，腺相关病毒8（AAV 8）介导的PCSK 9（AAV 8-PCSK 9）过表达可诱导脂血症并促进动脉粥样硬化。我们的目的是评估AAV 8-PCSK 9注射的C57 BL/6小鼠是否可以作为代谢综合征和动脉粥样硬化联合模型。C57 BL/6小鼠接受AAV-PCSK 9静脉注射，性别和年龄匹配的Ldlr−/−和C57 BL/6对照小鼠接受HFD-C或普通饲料喂养20周（分别为B6-PCSK 9-HFD-C、Ldlr−/− HFD-C、B6-HFD-C和B6-Chow）。与B6-Chow对照组相比，高脂饮食加胆固醇喂养导致B6-PCSK 9-HFD-C小鼠胰岛素抵抗和葡萄糖清除受损。B6-PCSK 9-HFD-C小鼠代谢健康的下降以及动脉粥样硬化的发展与Ldlr−/− HFD-C小鼠相似。重要的是，与B6-Chow对照相比，HFD-C喂养诱导B6-PCSK 9-HFD-C和B6-HFD-C中的胰岛增生。与代谢表型的改变一致，与B6-Chow对照相比，B6-PCSK 9-HFD-C和B6-HFD-C的脂肪组织中促炎性Ly 6Chigh/med单核细胞数量增加。高脂肪饮食与添加的胆固醇喂养的AAV-PCSK 9注射的C57 BL/6小鼠可以作为一个有用的模型，综合代谢综合征和动脉粥样硬化，不需要遗传操作。具有显著结果的研究设计示意图。与未注射HFD-C的对照小鼠相比，具有由AAV-PCSK 9注射与添加胆固醇的高脂肪饮食（HFD-C）配对诱导的高胆固醇血症的小鼠显示出类似的葡萄糖耐受不良和胰岛素抵抗特征，尽管具有晚期动脉粥样硬化。值得注意的是，与流行的代谢综合征和动脉粥样硬化的HFD-C喂食Ldlr−/−模型相比，喂食HFD-C的AAV-PCSK 9小鼠模拟了代谢缺陷。
Mouse models with genetic modifications are required to investigate atherogenesis and associated metabolic syndrome. Adeno-associated virus-8 (AAV8)-mediated overexpression of PCSK9 (AAV8-PCSK9) induces hyperlipidaemia and promotes atherosclerosis in C57BL/6 mice. We aimed to assess whether AAV8-PCSK9-injected C57BL/6 mice fed high-fat diet with added cholesterol (HFD-C) would serve as a model of combined metabolic syndrome and atherosclerosis. C57BL/6 mice received i.v. injection of AAV-PCSK9 and sex- and age-matched Ldlr−/− and C57BL/6 control mice were placed on HFD-C or chow diet for 20 weeks (B6-PCSK9-HFD-C, Ldlr−/− HFD-C, B6-HFD-C, and B6-Chow, respectively). High-fat diet with added cholesterol feeding led to insulin resistance and impaired glucose clearance in B6-PCSK9-HFD-C mice compared with B6-Chow controls. This decrease in metabolic health in B6-PCSK9-HFD-C mice as well as the development of atherosclerosis was similar to Ldlr−/− HFD-C mice. Importantly, HFD-C feeding induced pancreatic islet hyperplasia in B6-PCSK9-HFD-C and B6-HFD-C compared with B6-Chow controls. In line with alterations in the metabolic phenotype, there was an increase in the number of pro-inflammatory Ly6Chigh/med monocytes within the adipose tissues of B6-PCSK9-HFD-C and B6-HFD-C compared with B6-Chow controls. High-fat diet with added cholesterol-fed AAV-PCSK9-injected C57BL/6 mice can serve as a useful model of integrated metabolic syndrome and atherosclerosis that does not require genetic manipulations. Schematic illustration of the study design with notable results. Mice with hypercholesterolemia induced by AAV-PCSK9 injection paired with high-fat diet with added cholesterol (HFD-C) display similar glucose intolerance and insulin resistance profiles compared to non-injected HFD-C fed control mice, despite having advanced atherosclerosis. Notably, AAV-PCSK9 mice fed HFD-C have mimic the metabolic deficiencies compared with popular HFD-C fed Ldlr−/− model of metabolic syndrome and atherosclerosis.