Abstract
BackgroundHigh levels of apolipoprotein C3 (APOC3) can lead to hypertriglyceridemia, which increases the risk of cardiovascular disease. We aim to create APOC3-knockout (KO) rabbits and explore the effects of APOC3 deletion on the occurrence and development of atherosclerosis.MethodsAn sgRNA anchored to exon 2 of APOC3 was designed to edit embryo genomes using the CRISPR/Cas9 system. The founder rabbits were sequenced, and their lipid profile, inflammatory cytokines, and atherosclerotic plaques were analyzed.ResultsWhen given a normal chow (NC) diet, all APOC3-KO rabbits had 50% lower triglyceride (TG) levels than those of the matched age control group. Additionally, their plasma lipoprotein lipase increased. When fed a high-fat diet, APOC3 deficiency was observed to be more conducive to the maintenance of plasma TG, total cholesterol, and low-density lipoprotein cholesterol levels, and the inhibition of the inflammatory response and the protection against atherosclerosis in rabbits.ConclusionAPOC3 deficiency can delay the formation of atherosclerosis-induced HFD in rabbits, indicating this is a novel therapeutic target to treat atherosclerosis.
Highlights
apolipoprotein C3 (APOC3) is a key regulator of plasma triglycerides (TG) and shows significant correlation with plasma very lowdensity lipoprotein (VLDL) levels [1, 2]
We designed our exon 2-anchored CRISPR/ Cas9 system to generate APOC3-KO rabbits with biallelic mutations to study the relationship between APOC3 deficiency, abnormal lipid metabolism, and the formation and development of atherosclerosis in this study
Cas9 mRNA and sgRNA preparation To design mutant loci of the rabbit APOC3 gene, we obtained sequences from NCBI and designed CRISPR/Cas9 single-guide RNAs using the tool provided on the website: http://crispr.mit. edu
Summary
APOC3 is a key regulator of plasma triglycerides (TG) and shows significant correlation with plasma very lowdensity lipoprotein (VLDL) levels [1, 2]. (Oryctolagus cuniculus) continue to play significant roles in the study of lipid metabolism and histopathology [8]. CRISPR/Cas is machinery for editing genomes that forms a natural part of the bacterial defense mechanism and has been developed as a tool for genetic manipulation in mice [9], rabbits [10, 11], dogs [12], hamsters [13], etc. CRISPR-mediated genome editing is emerging as a therapeutic strategy for combating cardiovascular diseases [16]. We designed our exon 2-anchored CRISPR/ Cas system to generate APOC3-KO rabbits with biallelic mutations to study the relationship between APOC3 deficiency, abnormal lipid metabolism, and the formation and development of atherosclerosis in this study. High levels of apolipoprotein C3 (APOC3) can lead to hypertriglyceridemia, which increases the risk of cardiovascular disease. We aim to create APOC3-knockout (KO) rabbits and explore the effects of APOC3 deletion on the occurrence and development of atherosclerosis
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