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Sci Rep. 2019 Feb 22;9(1):2628. doi: 10.1038/s41598-019-38732-2.

Knockout rat models mimicking human atherosclerosis created by Cpf1-mediated gene targeting.

Lee JG1,2,3, Ha CH2,4, Yoon B2, Cheong SA1, Kim G1,2,4, Lee DJ2, Woo DC1,2,4, Kim YH5, Nam SY3, Lee SW6,7, Sung YH8,9,10, Baek IJ11,12,13.

Author information

1
ConveRgence mEDIcine research cenTer (CREDIT), Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea.
2
Biomedical Research Center, Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea.
3
College of Veterinary Medicine, Chungbuk National University, Cheongju, Republic of Korea.
4
Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
5
Department of Cardiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
6
ConveRgence mEDIcine research cenTer (CREDIT), Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea. lsw@amc.seoul.kr.
7
Department of Radiation Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea. lsw@amc.seoul.kr.
8
ConveRgence mEDIcine research cenTer (CREDIT), Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea. yhsung@amc.seoul.kr.
9
Biomedical Research Center, Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea. yhsung@amc.seoul.kr.
10
Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea. yhsung@amc.seoul.kr.
11
ConveRgence mEDIcine research cenTer (CREDIT), Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea. ijbaek@amc.seoul.kr.
12
Biomedical Research Center, Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea. ijbaek@amc.seoul.kr.
13
Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea. ijbaek@amc.seoul.kr.

Abstract

The rat is a time-honored traditional experimental model animal, but its use is limited due to the difficulty of genetic modification. Although engineered endonucleases enable us to manipulate the rat genome, it is not known whether the newly identified endonuclease Cpf1 system is applicable to rats. Here we report the first application of CRISPR-Cpf1 in rats and investigate whether Apoe knockout rat can be used as an atherosclerosis model. We generated Apoe- and/or Ldlr-deficient rats via CRISPR-Cpf1 system, characterized by high efficiency, successful germline transmission, multiple gene targeting capacity, and minimal off-target effect. The resulting Apoe knockout rats displayed hyperlipidemia and aortic lesions. In partially ligated carotid arteries of rats and mice fed with high-fat diet, in contrast to Apoe knockout mice showing atherosclerotic lesions, Apoe knockout rats showed only adventitial immune infiltrates comprising T lymphocytes and mainly macrophages with no plaque. In addition, adventitial macrophage progenitor cells (AMPCs) were more abundant in Apoe knockout rats than in mice. Our data suggest that the Cpf1 system can target single or multiple genes efficiently and specifically in rats with genetic heritability and that Apoe knockout rats may help understand initial-stage atherosclerosis.

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