{"doi":"10.1016/j.jlr.2022.100174","title":"Comparison between genetic and pharmaceutical disruption of Ldlr expression for the development of atherosclerosis","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.","journal":"Journal of Lipid Research","year":2022,"id":281103,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9567,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":318880,"name":"Shari Wang","orcid":null,"position":1,"is_corresponding":false},{"id":318879,"name":"Leela Goodspeed","orcid":null,"position":2,"is_corresponding":false},{"id":955954,"name":"Katherine E. Turk","orcid":"0000-0002-5024-8317","position":3,"is_corresponding":false},{"id":444467,"name":"Tomasz Wietecha","orcid":null,"position":4,"is_corresponding":false},{"id":955955,"name":"Yong-Jun Liu","orcid":"0000-0003-4325-2964","position":5,"is_corresponding":false},{"id":299555,"name":"Karin Bornfeldt","orcid":"0000-0001-9208-6523","position":6,"is_corresponding":false},{"id":244896,"name":"Kevin D. O’Brien","orcid":"0000-0002-2293-9196","position":7,"is_corresponding":false},{"id":105905,"name":"Alan Chait","orcid":"0000-0002-5903-2205","position":8,"is_corresponding":false},{"id":105906,"name":"Laura J. den Hartigh","orcid":"0000-0002-6789-5916","position":9,"is_corresponding":false},{"id":955953,"name":"D. Gomes","orcid":"0000-0002-4115-2428","position":0,"is_corresponding":true}],"reference_count":38,"raw_metadata":null,"created_at":"2026-07-19T00:29:07.472902Z","pmid":"35101425","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}