1. Hyperlipidemia induces typical atherosclerosis development in Ldlr and Apoe deficient rats
- Author
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Yufang Xiao, Mingyao Liu, Xueqin Cui, Yongliang Zhao, Tongtong Wang, Yiqing Yang, Ling Xie, Huaqing Chen, Wenhui Peng, Dali Li, Panpan You, Li Zeng, and Roumei Xing
- Subjects
Male ,0301 basic medicine ,Apolipoprotein E ,medicine.medical_specialty ,Time Factors ,Normal diet ,Aortic Diseases ,Hyperlipidemias ,Diet, High-Fat ,Proinflammatory cytokine ,Rats, Sprague-Dawley ,Gene Knockout Techniques ,03 medical and health sciences ,Apolipoproteins E ,Sex Factors ,Internal medicine ,Hyperlipidemia ,medicine ,Animals ,Genetic Predisposition to Disease ,Aorta, Abdominal ,Gene Editing ,business.industry ,Fatty liver ,Atherosclerosis ,medicine.disease ,Plaque, Atherosclerotic ,Fatty Liver ,Disease Models, Animal ,Mononuclear cell infiltration ,Phenotype ,030104 developmental biology ,Endocrinology ,Receptors, LDL ,LDL receptor ,Disease Progression ,Female ,lipids (amino acids, peptides, and proteins) ,Endothelium, Vascular ,CRISPR-Cas Systems ,Inflammation Mediators ,Rats, Transgenic ,Cardiology and Cardiovascular Medicine ,business ,Lipoprotein - Abstract
Background and aims Low-density lipoprotein receptor (Ldlr) and apolipoprotein E (Apoe) knockout (KO) mice have been widely used as animal models of atherosclerosis. However, data suggested that it is difficult to develop typical atherosclerosis in rats. To this end, Ldlr and Apoe KO rats were generated and the potential to develop novel atherosclerosis models was evaluated. Methods We established Apoe/Ldlr single and double KO (DKO) rats via the CRISPR/Cas9 system in the same background. Phenotypes of dyslipidemia and atherosclerosis in these KO rats were systematically characterized. Results Knockout of either gene led to severe dyslipidemia and liver steatosis. Significant atherosclerotic plaques were observed in the abdominal aorta of all mutant rats fed a normal diet for 48 weeks. Western diet greatly aggravated atherosclerosis and fatty liver. In addition, we found mononuclear cell infiltration in early lesions. Increased expression of inflammatory cytokines, as well as macrophage accumulation in lesions of mutants, was observed, indicating that mononuclear cell trafficking and endothelial inflammation affected atherogenesis. Moreover, mutant rats displayed a sex difference profile more similar to humans in which males had heavier plaque burdens than females. Conclusions Deficiency of either Ldlr or Apoe genes induced hyperlipidemia, which promoted endothelial inflammation and led to typical atherosclerosis in rats on normal or Western diets. These models display certain advantages, which will benefit future investigations of atherosclerotic pathology and antiatherosclerotic therapeutics.
- Published
- 2018