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

Abstract

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.

• Authors: Hui Zhao, Jianping Zhao, Di Wu, Zhaolin Sun, Yang Hua, Min Zheng, Yumei Liu, Qi Yang, Xiahe Huang, Yuan Li, Yueshan Piao, Yingchun Wang, Sin Man Lam, Huijuan Xu, Guanghou Shui, Yongjun Wang, Haifeng Yao, Liangxue Lai, Zhuo Du, Jidong Mi, Enqi Liu, Xunming Ji, Yong Q Zhang
• Journal: Science China. Life sciences (Sci China Life Sci) Vol. 65 Issue 7 Pg. 1342-1356 (07 2022) ISSN: 1869-1889 [Electronic] China
• PMID: 34705220 (Publication Type: Journal Article)
• Copyright: © 2021. Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature.

Chemical References

• Apolipoproteins E
• Cholesterol

Topics

• Animals
• Apolipoproteins E (genetics)
• Atherosclerosis (genetics, metabolism)
• Cholesterol
• Disease Models, Animal
• Dogs (genetics)
• Humans
• Hypercholesterolemia (complications, genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Plaque, Atherosclerotic (genetics)
• Rats