A novel mouse model of familial combined hyperlipidemia and atherosclerosis  

作　　者：Mei-jie Chen Yi-tong Xu Lu Sun Zhi-hua Wang Peter J.Little Li Wang Xun-de Xian Jian-ping Weng Suo-wen Xu 

机构地区：[1]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 [2]Institute of Cardiovascular Sciences,State Key Laboratory of Vascular Homeostasis and Remodeling,School of Basic Medical Sciences,Peking University,Beijing,100091,China [3]School of Pharmacy,Pharmacy Australia Centre of Excellence,The University of Queensland,Woolloongabba,QLD,4102,Australia [4]Department of Biomedical Sciences,City University of Hong Kong,Hong Kong,China

出　　处：《Acta Pharmacologica Sinica》2024年第6期1316-1320,共5页中国药理学报（英文版）

基　　金：supported by grants from the National Key R&D Program of China(Grant No.2021YFC2500500);the National Natural Science Foundation of China(Grant No.82370444,82070464,82003741,82270479,82070460);the Strategic Priority Research Program of the Chinese Academy of Sciences(Grant No.XDB38010100);supported by the Program for Innovative Research Team of The First Affiliated Hospital of USTC(CXGG02);Anhui Provincial Key Research and Development Program(Grant No.202104j07020051);Anhui Provincial Natural Science Foundation(Grant No.2208085J08).

摘　　要：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^(-1)·d^(-1))and fenofibrate(100 mg·kg^(-1)·d^(-1)).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.

关 键 词：familial combined hyperlipidemia ApoC3 mouse model LIPID-LOWERING ATHEROSCLEROSIS 

分 类 号：R96[医药卫生—药理学]