ApoE is an important component of plasma lipoprotein and is closely related to cholesterol metabolism. Low expression or absence of ApoE contributes to increasing blood lipid levels which would induce atherosclerosis. The ApoE KO dog model is generated using CRISPR/Cas 9 and somatic cell cloning techniques.
Compared with wild type (WT), the ApoE mutant canine model has obvious pathological changes of atherosclerosis. MRI and ultrasound results show obvious ischemic infarction, internal carotid artery plaque and vascular stenosis in the brain.
ApoE KO dogs exhibit a hyperlipidemic phenotype with high cholesterol and LDL after birth
The results of the vascular ultrasound showed atherosclerotic plaques were detected in the posterior wall of the initial segment of the left and right internal carotid arteries, respectively. Oscillatory blood flow and stenosis were observed in the internal carotid artery of ApoE KO dogs. MRI results showed cerebral infarction in ApoE KO dogs.
Coronary artery stenosis and myocardial ischemia and hypoxia lead to myocardial fibrosis and ventricular dilatation in ApoE KO dogs. Owing to atherosclerosis and stenosis of the iliac artery and the femoral artery, blood supply to the rear limbs is insufficient in ApoE KO dogs, resulting in occlusion of the dorsalis pedis artery and gangrene of the rear limbs.
There are a large number of red blood cells (indicated by "*"), cholesterol crystals (indicated by "♦") and plaques in the lumen of the left internal carotid artery of ApoEgene-edited dogs (Figure B). Substantial thickening of the tunica intima layer filled with foam cells is apparent in the basilar artery, and a large number of small vacuoles in the cytoplasm (indicated by "# "), and nearly occluded lumen are also observed (Figure D).
Traditional atherosclerosis models need to be induced through external methods such as high-fat diet. For the first time, SGene has successfully developed a canine model of atherosclerosis through gene editing, which exhibits a wide range of phenotypes such as vascular stenosis, plaques, and subsequently atherosclerosis. Clinical symptoms such as cerebral infarction can simulate the occurrence and development of human atherosclerotic disease, and is an ideal model for the early discovery, efficacy evaluation and device evaluation of such innovative drugs.
Working with various research institutes such as Institute of Fuwai Cardiovascular Disease of the Chinese Academy of Sciences, as well as pharmaceutical companies like Inno Medicine Co., Ltd. to evaluate the pathogenesis of ApoE mutant dogs in atherosclerosis, stroke and other related diseases, and to evaluate new therapies for atherosclerosis, stroke and other related diseases (including endovascular surgery).
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