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Updated: Oct 5, 2025
Quantification of Atherosclerosis in Mice
Published on: June 12, 2019
Comparison between genetic and pharmaceutical disruption of Ldlr expression for the development of atherosclerosis
Diego Gomes1, Shari Wang1, Leela Goodspeed1
1Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington, Seattle, WA, USA; Diabetes Institute, University of Washington, Seattle, WA, USA.
Abstract:
Antisense oligonucleotides (ASOs) against Ldl receptor (Ldlr-ASO) represent a promising strategy to promote hypercholesterolemic atherosclerosis in animal models without the need for complex breeding strategies. Here, we sought to characterize and contrast atherosclerosis in mice given Ldlr-ASO with those bearing genetic Ldlr deficiency. To promote atherosclerosis, male and female C57Bl6/J mice were either given weekly injections of Ldlr-ASO (5 mg/kg once per week) or genetically deficient in Ldlr (Ldlr-/-). Mice consumed either standard rodent chow or a diet high in saturated fat and sucrose with 0.15% added cholesterol for 16 weeks. While both models of Ldlr deficiency promoted hypercholesterolemia, Ldlr-/- mice exhibited nearly 2-fold higher cholesterol levels than Ldlr-ASO mice, reflected by increased VLDL and LDL levels. Consistent with this, the en face atherosclerotic lesion area was 3-fold and 3.6-fold greater in male and female mice with genetic Ldlr deficiency, respectively, as compared with the modest atherosclerosis observed following Ldlr-ASO treatment. Aortic sinus lesion sizes, fibrosis, smooth muscle actin, and necrotic core areas were also larger in Ldlr-/- mice, suggesting a more advanced phenotype. Despite a more modest effect on hypercholesterolemia, Ldlr-ASO induced greater hepatic inflammatory gene expression, macrophage accumulation, and histological lobular inflammation than was observed in Ldlr-/- mice. We conclude Ldlr-ASO is a promising tool for the generation of complex rodent models with which to study atherosclerosis but does not promote comparable levels of hypercholesterolemia or atherosclerosis as Ldlr-/- mice and increases hepatic inflammation. Thus, genetic Ldlr deficiency may be a superior model, depending on the proposed use.
Insights
Antisense oligonucleotides (ASOs) targeting the Ldl receptor (Ldlr-ASO) induce hypercholesterolemia and atherosclerosis. However, genetic Ldlr deficiency causes more severe atherosclerosis and higher cholesterol levels than Ldlr-ASO treatment.
Area of Science:
- Cardiovascular Research
- Animal Models of Atherosclerosis
- Pharmacology
Background:
- Antisense oligonucleotides (ASOs) targeting the Ldl receptor (Ldlr-ASO) offer a method to induce hypercholesterolemia and atherosclerosis in animal models.
- Genetic deficiency in the Ldl receptor (Ldlr-/-) is a well-established model for studying atherosclerosis.
Purpose of the Study:
- To characterize and contrast atherosclerosis development in mice treated with Ldlr-ASO versus genetically Ldlr-deficient mice.
- To evaluate the impact of diet and Ldlr deficiency models on hypercholesterolemia and atherosclerotic lesion progression.
Main Methods:
- Male and female C57Bl6/J mice were administered either Ldlr-ASO (5 mg/kg weekly) or were genetically Ldlr-deficient (Ldlr-/-).
- Mice were fed either a standard rodent chow or a high-fat, high-sucrose diet with added cholesterol for 16 weeks.
- Atherosclerosis was assessed by measuring en face lesion area, aortic sinus lesion size, and histological parameters.
Main Results:
- Both Ldlr-ASO and Ldlr-/- models induced hypercholesterolemia and atherosclerosis.
- Ldlr-/- mice exhibited significantly higher cholesterol levels (nearly 2-fold) and larger atherosclerotic lesion areas (3-3.6 fold) compared to Ldlr-ASO treated mice.
- Ldlr-ASO treatment resulted in greater hepatic inflammation, macrophage accumulation, and lobular inflammation compared to Ldlr-/- mice.
Conclusions:
- Ldlr-ASO is a viable tool for generating complex rodent models of atherosclerosis but does not replicate the severity of hypercholesterolemia or atherosclerosis seen in Ldlr-/- mice.
- Genetic Ldlr deficiency may be a superior model for studying advanced atherosclerosis, depending on research objectives.
- Ldlr-ASO treatment uniquely exacerbates hepatic inflammation, suggesting distinct biological effects beyond LDL receptor blockade.
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