Dogs lacking Apolipoprotein E show advanced atherosclerosis leading to apparent clinical complications

Atherosclerotic cardiovascular disease resulting from dysregulated lipid metabolism is the leading cause of morbidity and mortality worldwide. Apolipoprotein E (ApoE) plays a critical role in cholesterol metabolism. Knockouts in lipid-metabolizing proteins including ApoE in multiple model organisms...

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Bibliographic Details
Published in:Science China. Life sciences 2022-07, Vol.65 (7), p.1342-1356
Main Authors: Zhao, Hui, Zhao, Jianping, Wu, Di, Sun, Zhaolin, Hua, Yang, Zheng, Min, Liu, Yumei, Yang, Qi, Huang, Xiahe, Li, Yuan, Piao, Yueshan, Wang, Yingchun, Lam, Sin Man, Xu, Huijuan, Shui, Guanghou, Wang, Yongjun, Yao, Haifeng, Lai, Liangxue, Du, Zhuo, Mi, Jidong, Liu, Enqi, Ji, Xunming, Zhang, Yong Q.
Format: Article
Language:English
Subjects:
Animal models
Apolipoprotein E
Apolipoproteins
Arteries
Arteriosclerosis
Atherosclerosis
Biomedical and Life Sciences
Cardiovascular diseases
Cardiovascular system
Cholesterol
CRISPR
Gangrene
Hypercholesterolemia
Ischemia
Life Sciences
Lipid metabolism
Metabolism
Morbidity
Mutants
Nuclear transfer
Occlusion
Plaques
Research Paper
Somatic cell nuclear transfer
Stenosis
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Summary:Atherosclerotic cardiovascular disease resulting from dysregulated lipid metabolism is the leading cause of morbidity and mortality worldwide. Apolipoprotein E (ApoE) plays a critical role in cholesterol metabolism. Knockouts in lipid-metabolizing proteins including ApoE in multiple model organisms such as mice and rats exhibiting elevated levels of cholesterol have been widely used for dissecting the pathology of atherosclerosis, but few of these animal models exhibit advanced atherosclerotic plaques leading to ischemia-induced clinical symptoms, limiting their use for translational studies. Here we report hypercholesterolemia and severe atherosclerosis characterized by stenosis and occlusion of arteries, together with clinical manifestations of stroke and gangrene, in ApoE knockout dogs generated by CRISPR/Cas9 and cloned by somatic cell nuclear transfer technologies. Importantly, the hypercholesterolemia and atherosclerotic complications in F0 mutants are recapitulated in their offspring. As the ApoE-associated atherosclerosis and clinical manifestations in mutant dogs are more similar to that in human patients compared with those in other animal models, these mutant dogs will be invaluable in developing and evaluating new therapies, including endovascular procedures, against atherosclerosis and related disorders.
ISSN:1674-7305
1869-1889
DOI:10.1007/s11427-021-2006-y