Hyperlipidemia induces typical atherosclerosis development in Ldlr and Apoe deficient rats.

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.

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