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A severe atherosclerosis mouse model on the resistant NOD background
- Source :
- Disease Models & Mechanisms, Vol 11, Iss 10 (2018), Disease Models & Mechanisms
- Publication Year :
- 2018
- Publisher :
- The Company of Biologists, 2018.
-
Abstract
- 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.<br />Summary: Double knockout of Apoe and Ldlr on the highly atherosclerosis-resistant NOD mouse background results in severe atherosclerosis, which paves the way for the study of severe atherosclerosis in the setting of autoimmunity.
- Subjects :
- 0301 basic medicine
Apolipoprotein E
Male
Neuroscience (miscellaneous)
Medicine (miscellaneous)
lcsh:Medicine
Hyperlipidemias
Nod
medicine.disease_cause
General Biochemistry, Genetics and Molecular Biology
Autoimmunity
03 medical and health sciences
Apolipoproteins E
Immunology and Microbiology (miscellaneous)
Mice, Inbred NOD
CRISPR-Associated Protein 9
Hyperlipidemia
Genetic model
lcsh:Pathology
Medicine
Animals
CRISPR/Cas9
NOD
NOD mice
Mice, Knockout
Base Sequence
business.industry
lcsh:R
medicine.disease
Atherosclerosis
Mice, Inbred C57BL
Disease Models, Animal
030104 developmental biology
LDLR
Receptors, LDL
Immunology
LDL receptor
Female
lipids (amino acids, peptides, and proteins)
CRISPR-Cas Systems
business
Gene Deletion
Lipoprotein
Research Article
ApoE
lcsh:RB1-214
Subjects
Details
- Language :
- English
- ISSN :
- 17548411 and 17548403
- Volume :
- 11
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- Disease Models & Mechanisms
- Accession number :
- edsair.doi.dedup.....d13b9e2934df66be044dec44a78558ce