Apolipoprotein E deficiency accelerates atherosclerosis development in miniature pigs

• DOI: 10.1242/dmm.036632
• Publication Date: 2018-10-10T10:25:54Z
• Authors: Bin Fang; Xueyang Ren; Ying Wang; Ze Li; Lihua Zhao; Manling Zhang; Chu Li; Zhengwei Zhang; Lei Chen; Xiaoxue Li; Jiying Liu; Qiang Xiong; Lining Zhang; Yong Jin; Xiaorui Liu; Lin Li; Hong Wei; Haiyuan Yang; Rongfeng Li; Yifan Dai
• Keywords: 0301 basic medicine; Nuclear Transfer Techniques; Swine; RNA, Guide, CRISPR-Cas Systems; Diet, High-Fat; Animals, Genetically Modified; Hyperlipoproteinemia Type II; 03 medical and health sciences; Apolipoproteins E; Fetus; INDEL Mutation; CRISPR-Associated Protein 9; Pathology; RB1-214; Animals; Resource Article; CRISPR/Cas9; Triglycerides; 2. Zero hunger; Base Sequence; R; Feeding Behavior; Fibroblasts; Atherosclerosis; 3. Good health; Cholesterol; Phenotype; Bama miniature pigs; Medicine; Swine, Miniature; CRISPR-Cas Systems; ApoE

ABSTRACT Miniature pigs have advantages over rodents in modeling atherosclerosis because their cardiovascular system and physiology are similar to that of humans. Apolipoprotein E (ApoE) deficiency has long been implicated in cardiovascular disease in humans. To establish an improved large animal model of familial hypercholesterolemia and atherosclerosis, the clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 system (CRISPR/Cas9) was used to disrupt the ApoE gene in Bama miniature pigs. Biallelic-modified ApoE pigs with in-frame mutations (ApoEm/m) and frameshift mutations (ApoE−/−) were simultaneously produced. ApoE−/− pigs exhibited moderately increased plasma cholesterol levels when fed with a regular chow diet, but displayed severe hypercholesterolemia and spontaneously developed human-like atherosclerotic lesions in the aorta and coronary arteries after feeding on a high-fat and high-cholesterol (HFHC) diet for 6 months. Thus, these ApoE−/− pigs could be valuable large animal models for providing further insight into translational studies of atherosclerosis.