Department of Endocrinology, Institute of Endocrine and Metabolic Disease, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, 230022, China.
Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences, Peking University, Beijing, 100091, China.
Acta Pharmacol Sin. 2024 Jun;45(6):1316-1320. doi: 10.1038/s41401-024-01241-8. Epub 2024 Mar 8.
Within the context of residual cardiovascular risk in post-statin era, emerging evidence from epidemiologic and human genetic studies have demonstrated that triglyceride (TG)-rich lipoproteins and their remnants are causally related to cardiovascular risk. While, carriers of loss-of-function mutations of ApoC3 have low TG levels and are protected from cardiovascular disease (CVD). Of translational significance, siRNAs/antisense oligonucleotide (ASO) targeting ApoC3 is beneficial for patients with atherosclerotic CVD. Therefore, animal models of atherosclerosis with both hypercholesterolemia and hypertriglyceridemia are important for the discovery of novel therapeutic strategies targeting TG-lowering on top of traditional cholesterol-lowering. In this study, we constructed a novel mouse model of familial combined hyperlipidemia through inserting a human ApoC3 transgene (hApoC3-Tg) into C57BL/6 J mice and injecting a gain-of-function variant of adeno-associated virus-proprotein convertase subtilisin/kexin type 9 (AAV-PCSK9)-D377Y concurrently with high cholesterol diet (HCD) feeding for 16 weeks. In the last 10 weeks, hApoC3-Tg mice were orally treated with a combination of atorvastatin (10 mg·kg·d) and fenofibrate (100 mg·kg·d). HCD-treated hApoC3-Tg mice demonstrated elevated levels of serum TG, total cholesterol (TC) and low density lipoprotein-cholesterol (LDL-C). Oral administration of atorvastatin and fenofibrate significantly decreased the plaque sizes of en face aorta, aortic sinus and innominate artery accompanied by improved lipid profile and distribution. In summary, this novel mouse model is of considerable clinical relevance for evaluation of anti-atherosclerotic drugs by targeting both hypercholesterolemia and hypertriglyceridemia.
在他汀类药物治疗后残余心血管风险的背景下，来自流行病学和人类遗传学研究的新证据表明，富含甘油三酯（TG）的脂蛋白及其残粒与心血管风险有因果关系。而载脂蛋白 C3（ApoC3）功能丧失突变的携带者 TG 水平较低，并且可以预防心血管疾病（CVD）。具有转化意义的是，靶向 ApoC3 的小干扰 RNA（siRNA）/反义寡核苷酸（ASO）对动脉粥样硬化性 CVD 患者有益。因此，同时具有高胆固醇血症和高甘油三酯血症的动脉粥样硬化动物模型对于发现针对降低 TG 的新型治疗策略具有重要意义，这些策略可在传统降胆固醇治疗的基础上进行。在这项研究中，我们通过将人载脂蛋白 C3 转基因（hApoC3-Tg）插入 C57BL/6J 小鼠，并在高胆固醇饮食（HCD）喂养的同时注射腺相关病毒-前蛋白转化酶枯草溶菌素 9（AAV-PCSK9）-D377Y 的功能获得性变体，构建了一种新型家族性混合性高脂血症小鼠模型，持续 16 周。在最后 10 周，hApoC3-Tg 小鼠接受阿托伐他汀（10mg·kg·d）和非诺贝特（100mg·kg·d）联合口服治疗。HCD 处理的 hApoC3-Tg 小鼠血清 TG、总胆固醇（TC）和低密度脂蛋白胆固醇（LDL-C）水平升高。阿托伐他汀和非诺贝特的口服给药显著减少了主动脉正面、主动脉窦和无名动脉的斑块大小，同时改善了血脂谱和分布。总之，该新型小鼠模型对于评估针对高胆固醇血症和高甘油三酯血症的抗动脉粥样硬化药物具有重要的临床意义。
