Abstract
Coronary atherosclerotic disease is a serious disease in humans, but no suitable animal model is available currently for further studies. We used apolipoprotein E gene knockout (ApoE KO) rats to induce hypercholesterolemia through a special high cholesterol/bile salt diet (Paigen diet), then analyzed aortic and coronary atherosclerosis lesions and the myocardial injury in order to establish a novel small animal model of coronary atherosclerosis. Plasma cholesterol of ApoE KO rats increased 7.6-fold compared with wild-type rats after 8 weeks on the Paigen diet. After 10 to 12 weeks of subsisting on the Paigen diet, ApoE KO rats developed mild aortic atherosclerosis with severe coronary atherosclerosis. Hematoxilyn and eosin staining showed that 11 out of 12 ApoE KO male rats had right coronary artery atherosclerosis, 7 of them were>70% occluded. Oil Red O (Lipid Stain), Mac2 immuno-staining and Masson’s trichrome staining demonstrated substantial amounts of lipid, macrophages and collagen fibers in coronary atherosclerosis plaques. In addition, ApoE KO male rats had severe myocardial focal lesions with cholesterol ester as the main component in the lesions. In conclusion, ApoE KO rats developed severe hypercholesterolemia, coronary atherosclerosis and myocardial cholesterol ester deposition after subsisting on the Paigen diet and can be used as a novel animal model for studies on cholesterol metabolism and coronary atherosclerotic disease.
Highlights
Coronary atherosclerotic disease (CAD) is a human disease with a high morbidity and mortality
It was hard to generate gene knockout rats based on the traditional method using ES cell homologous recombination
The plasma cholesterol levels of apolipoprotein E gene knockout (ApoE KO) rats were 1.5-fold higher than wild type (WT) controls, but significantly lower than ApoE KO mice, which are consistent with the present data
Summary
Coronary atherosclerotic disease (CAD) is a human disease with a high morbidity and mortality. High cholesterol diet can induce severe hypercholesterolemia and aortic atherosclerosis in ApoE KO mice. If we can promote the development of atherosclerosis through ApoE gene knockout, it is likely to induce more severe coronary atherosclerosis in rats. This type of rat may become a more suitable small animal model for human CAD research. ApoE knockout rats (ApoE KO), generated by transcriptional activator-like effector nucleases (TALEN) mediated gene editing method, were used to analyze their plasma lipid contents, aortic and coronary atherosclerotic lesions and myocardial injury produced by chow diet or Paigen diet feeding
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