Comparison between genetic and pharmaceutical disruption of Ldlr expression for the development of atherosclerosis

• DOI: 10.1016/j.jlr.2022.100174
• Publication Date: 2022-01-29T14:43:52Z
• Authors: Diego Gomes; Shari Wang; Leela Goodspeed; Katherine E. Turk; Tomasz Wietecha; Yongjun Liu; Karin E. Bornfeldt; Kevin D. O'Brien; Alan Chait; Laura J. den Hartigh
• Keywords: Male; Mice, Knockout; 0301 basic medicine; Hypercholesterolemia; QD415-436; liver; Atherosclerosis; Biochemistry; animal models; Mice, Inbred C57BL; Disease Models, Animal; Mice; 03 medical and health sciences; Cholesterol; Pharmaceutical Preparations; Receptors, LDL; inflammation; hyperlipidemia; Animals; Female; antisense oligonucleotides; receptors/lipoprotein; Research Article

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.