{"doi":"10.3389/fcvm.2022.818662","title":"Reduction of Stabilin-2 Contributes to a Protection Against Atherosclerosis","abstract":"We have previously identified a novel atherosclerosis quantitative trait locus (QTL), Arch atherosclerosis 5 ( Aath5 ), on mouse chromosome 10 by three-way QTL analyses between Apoe −/− mice on a DBA/2J, 129S6 and C57BL/6J background. The DBA/2J haplotype at the Aath5 locus was associated with smaller plaque size. One of the candidate genes underlying Aath5 was Stabilin-2 ( Stab2 ), which encodes a clearance receptor for hyaluronan (HA) predominantly expressed in liver sinusoidal endothelial cells (LSECs). However, the role of Stab2 in atherosclerosis is unknown. A congenic line of Apoe −/− mice carrying Aath5 covering the Stab2 DBA allele on a background of 129S6 confirmed the small reductions of atherosclerotic plaque development. To further determine whether Stab2 is an underlying gene for Aath5 , we generated Stab2 −/− Apoe −/− mice on a C57BL/6J background. When fed with a Western diet for 8 weeks, Stab2 −/− Apoe −/− males developed approximately 30% smaller plaques than Stab2 +/+ Apoe −/− mice. HA was accumulated in circulation but not in major organs in the Stab2 deficient mice. STAB2-binding molecules that are involved in atherosclerosis, including acLDL, apoptotic cells, heparin and vWF were not likely the direct cause of the protection in the Stab2 −/− Apoe −/− males. These data indicate that reduction of Stab2 is protective against atherosclerotic plaque development, and that Stab2 is a contributing gene underlying Aath5 , although its effect is small. To test whether non-synonymous amino acid changes unique to DBA/2J affect the function of STAB2 protein, we made HEK293 cell lines expressing STAB2 129 or STAB2 DBA proteins, as well as STAB2 129 proteins carrying each of five DBA-unique replacements that have been predicted to be deleterious. These mutant cells were capable of internalizing 125 I -HA and DiI-acLDL similarly to the control cells. These results indicate that the amino acid changes unique to DBA/2J are not affecting the function of STAB2 protein, and support our previous observation that the reduced transcription of Stab2 in the liver sinusoid as a consequence of the insertion of a viral-derived sequence, intracisternal A particle, is the primary contributor to the athero-protection conferred by the DBA/2J allele.","journal":"Frontiers in Cardiovascular Medicine","year":2022,"id":259627,"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":16,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9493,"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":912746,"name":"Connor A. Clanton","orcid":null,"position":1,"is_corresponding":false},{"id":633510,"name":"Amanda M. Lewis","orcid":null,"position":2,"is_corresponding":false},{"id":263718,"name":"Xinghui Sun","orcid":"0000-0002-1156-0375","position":3,"is_corresponding":false},{"id":422319,"name":"Sylvia Hiller","orcid":"0000-0001-6838-1178","position":4,"is_corresponding":false},{"id":912747,"name":"Phillip K Huynh","orcid":null,"position":5,"is_corresponding":false},{"id":462680,"name":"Jennifer Wilder","orcid":null,"position":6,"is_corresponding":false},{"id":462681,"name":"John R. Hagaman","orcid":null,"position":7,"is_corresponding":false},{"id":435873,"name":"Feng Li","orcid":"0000-0003-3169-6349","position":8,"is_corresponding":false},{"id":412512,"name":"Nobuyo Maeda-Smithies","orcid":null,"position":9,"is_corresponding":false},{"id":275859,"name":"Edward N. Harris","orcid":"0000-0001-7045-1040","position":10,"is_corresponding":false},{"id":411206,"name":"Yukako Kayashima","orcid":"0000-0003-3415-9135","position":0,"is_corresponding":true}],"reference_count":56,"raw_metadata":null,"created_at":"2026-07-19T00:25:58.993402Z","pmid":"35360009","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":[]}