A severe atherosclerosis mouse model on the resistant NOD background

Disease Models & Mechanisms

Qianqian Zheng¹  Jing Luo¹  Yinming Liang¹  Saichao Li¹  Liaoxun Lu¹  Xinhui Qi¹  Lichen Zhang¹  Yanrong Gu¹  Xugang Wang¹  Li Wang¹  Zhijun Chen¹  Tianzhu Chao¹  Wenping Zheng¹  Rong Huang¹  Yinhang Wen¹ 

[1] Laboratory of Genetic Regulators in the Immune System, Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Laboratory Medicine, Xinxiang Medical University, Henan Province 453003, China;

关键词: NOD;    Atherosclerosis;    CRISPR/Cas9;    ApoE;    LDLR;   

DOI  :  10.1242/dmm.033852

来源: DOAJ

【 摘 要 】

Atherosclerosis is a complex disease affecting arterial blood vessels and blood flow that could result in a variety of life-threatening consequences. Disease models with diverged genomes are necessary for understanding the genetic architecture of this complex disease. Non-obese diabetic (NOD) mice are highly polymorphic and widely used for studies of type 1 diabetes and autoimmunity. Understanding atherosclerosis development in the NOD strain is of particular interest as human atherosclerosis on the diabetic and autoimmune background has not been successfully modeled. In this study, we used CRISPR/Cas9 genome editing to genetically disrupt apolipoprotein E (ApoE) and low-density lipoprotein receptor (LDLR) expression on the pure NOD background, and compared phenotype between single-gene-deleted mice and double-knockout mutants with reference to ApoE-deficient C57BL/6 mice. We found that genetic ablation of Ldlr or Apoe in NOD mice was not sufficient to establish an atherosclerosis model, in contrast to ApoE-deficient C57BL/6 mice fed a high-fat diet (HFD) for over 12 weeks. We further obtained NOD mice deficient in both LDLR and ApoE, and assessed the severity of atherosclerosis and immune response to hyperlipidemia in comparison to ApoE-deficient C57BL/6 mice. Strikingly, the double-knockout NOD mice treated with a HFD developed severe atherosclerosis with aorta narrowed by over 60% by plaques, accompanied by destruction of pancreatic islets and an inflammatory response to hyperlipidemia. Therefore, we succeeded in obtaining a genetic model with severe atherosclerosis on the NOD background, which is highly resistant to the disease. This model is useful for the study of atherosclerosis in the setting of autoimmunity.

【 授权许可】

Unknown