{"doi":"10.7554/elife.103413","title":"Disruption of the novel nested gene Aff3ir mediates disturbed flow-induced atherosclerosis in mice","abstract":"<jats:p>\n                    Disturbed shear stress-induced endothelial atherogenic responses are pivotal in the initiation and progression of atherosclerosis, contributing to the uneven distribution of atherosclerotic lesions. This study investigates the role of\n                    <jats:italic>Aff3ir-ORF2</jats:italic>\n                    , a novel nested gene variant, in disturbed flow-induced endothelial cell activation and atherosclerosis. We demonstrate that disturbed shear stress significantly reduces\n                    <jats:italic>Aff3ir-ORF2</jats:italic>\n                    expression in athero-prone regions. Using three distinct mouse models with manipulated\n                    <jats:italic>Aff3ir-ORF2</jats:italic>\n                    expression, we demonstrate that\n                    <jats:italic>Aff3ir-ORF2</jats:italic>\n                    exerts potent anti-inflammatory and anti-atherosclerotic effects in\n                    <jats:italic>\n                      Apoe\n                      <jats:sup>-/-</jats:sup>\n                    </jats:italic>\n                    mice. RNA sequencing revealed that interferon regulatory factor 5 (\n                    <jats:italic>Irf5</jats:italic>\n                    ), a key regulator of inflammatory processes, mediates inflammatory responses associated with\n                    <jats:italic>Aff3ir-ORF2</jats:italic>\n                    deficiency.\n                    <jats:italic>Aff3ir-ORF2</jats:italic>\n                    interacts with\n                    <jats:italic>Irf5</jats:italic>\n                    , promoting its retention in the cytoplasm, thereby inhibiting the\n                    <jats:italic>Irf5</jats:italic>\n                    -dependent inflammatory pathways. Notably,\n                    <jats:italic>Irf5</jats:italic>\n                    knockdown in\n                    <jats:italic>Aff3ir-ORF2</jats:italic>\n                    deficient mice almost completely rescues the aggravated atherosclerotic phenotype. Moreover, endothelial-specific\n                    <jats:italic>Aff3ir-ORF2</jats:italic>\n                    supplementation using the CRISPR/Cas9 system significantly ameliorated endothelial activation and atherosclerosis. These findings elucidate a novel role for\n                    <jats:italic>Aff3ir-ORF2</jats:italic>\n                    in mitigating endothelial inflammation and atherosclerosis by acting as an inhibitor of\n                    <jats:italic>Irf5</jats:italic>\n                    , highlighting its potential as a valuable therapeutic approach for treating atherosclerosis.\n                  </jats:p>","journal":"eLife","year":2025,"id":642836,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":286449,"name":"Lei Huang","orcid":"0000-0003-4236-1448","position":1,"is_corresponding":false},{"id":1672307,"name":"Zhuozheng Chen","orcid":null,"position":2,"is_corresponding":false},{"id":1672308,"name":"Ze Yuan","orcid":null,"position":3,"is_corresponding":false},{"id":572912,"name":"Yue Zhao","orcid":"0000-0002-6818-2352","position":4,"is_corresponding":false},{"id":1672309,"name":"Lingfang Zeng","orcid":"0000-0002-0390-4561","position":5,"is_corresponding":false},{"id":63982,"name":"Yi Zhu","orcid":"0000-0002-5586-3773","position":6,"is_corresponding":false},{"id":1202480,"name":"Jinlong He","orcid":"0000-0001-7349-8135","position":7,"is_corresponding":false},{"id":1672306,"name":"Shuo He","orcid":"0009-0004-5912-9930","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Disruption of the novel nested gene Aff3ir mediates disturbed flow-induced atherosclerosis in mice","abstract":"<jats:p>\n                    Disturbed shear stress-induced endothelial atherogenic responses are pivotal in the initiation and progression of atherosclerosis, contributing to the uneven distribution of atherosclerotic lesions. This study investigates the role of\n                    <jats:italic>Aff3ir-ORF2</jats:italic>\n                    , a novel nested gene variant, in disturbed flow-induced endothelial cell activation and atherosclerosis. We demonstrate that disturbed shear stress significantly reduces\n                    <jats:italic>Aff3ir-ORF2</jats:italic>\n                    expression in athero-prone regions. Using three distinct mouse models with manipulated\n                    <jats:italic>Aff3ir-ORF2</jats:italic>\n                    expression, we demonstrate that\n                    <jats:italic>Aff3ir-ORF2</jats:italic>\n                    exerts potent anti-inflammatory and anti-atherosclerotic effects in\n                    <jats:italic>\n                      Apoe\n                      <jats:sup>-/-</jats:sup>\n                    </jats:italic>\n                    mice. RNA sequencing revealed that interferon regulatory factor 5 (\n                    <jats:italic>Irf5</jats:italic>\n                    ), a key regulator of inflammatory processes, mediates inflammatory responses associated with\n                    <jats:italic>Aff3ir-ORF2</jats:italic>\n                    deficiency.\n                    <jats:italic>Aff3ir-ORF2</jats:italic>\n                    interacts with\n                    <jats:italic>Irf5</jats:italic>\n                    , promoting its retention in the cytoplasm, thereby inhibiting the\n                    <jats:italic>Irf5</jats:italic>\n                    -dependent inflammatory pathways. Notably,\n                    <jats:italic>Irf5</jats:italic>\n                    knockdown in\n                    <jats:italic>Aff3ir-ORF2</jats:italic>\n                    deficient mice almost completely rescues the aggravated atherosclerotic phenotype. Moreover, endothelial-specific\n                    <jats:italic>Aff3ir-ORF2</jats:italic>\n                    supplementation using the CRISPR/Cas9 system significantly ameliorated endothelial activation and atherosclerosis. These findings elucidate a novel role for\n                    <jats:italic>Aff3ir-ORF2</jats:italic>\n                    in mitigating endothelial inflammation and atherosclerosis by acting as an inhibitor of\n                    <jats:italic>Irf5</jats:italic>\n                    , highlighting its potential as a valuable therapeutic approach for treating atherosclerosis.\n                  </jats:p>","is_dataset_classified":null,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"40315012","pmcid":"PMC12048156","openalex_id":"https://openalex.org/W4405372253","authors":[],"funders":[{"funder_name":"National Natural Science Foundation of China","grant_id":"82330012 and 82127808","title":null},{"funder_name":"National Natural Science Foundation of China","grant_id":"82422006","title":null},{"funder_name":"National Natural Science Foundation of China","grant_id":"32471166","title":null},{"funder_name":"National Natural Science Foundation of China","grant_id":"82270516","title":null},{"funder_name":"British Heart Foundation","grant_id":"FS-15/74/31669","title":null},{"funder_name":"Natural Science Foundation of Tianjin Municipality","grant_id":"24JCJQJC00060","title":null},{"funder_name":"Natural Science Foundation of Tianjin Municipality","grant_id":"21JCYBJC01590","title":null},{"funder_name":"Key Research Project in Traditional Chinese Medicine of Tianjin","grant_id":"2023013","title":null}],"total_grants":8,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[{"year":2026,"count":1}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://elifesciences.org/reviewed-preprints/103413.pdf","host_type":"journal"},{"url":"https://elifesciences.org/reviewed-preprints/103413.pdf","host_type":"publisher"},{"url":"https://cdn.elifesciences.org/articles/103413/elife-103413-v1.pdf","host_type":"publisher"},{"url":"https://cdn.elifesciences.org/articles/103413/elife-103413-v1.xml","host_type":"publisher"},{"url":"https://elifesciences.org/articles/103413","host_type":"publisher"},{"url":"https://doi.org/10.7554/elife.103413","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/40315012","host_type":"repository"},{"url":"https://doaj.org/article/b071ceff09d3477dbe027168a674d832","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/12048156","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC12048156","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC12048156?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["RNA modifications and cancer","Atherosclerosis and Cardiovascular Diseases","Galectins and Cancer Biology","Animals","Mice","Atherosclerosis","Endothelial Cells","Stress, Mechanical","Gene Knockdown Techniques","Nested Genes","Inflammation","Plaque, Atherosclerotic","Mice, Knockout, ApoE","Mice, Inbred C57BL","Humans","Human Umbilical Vein Endothelial Cells","Active Transport, Cell Nucleus","Interferon Regulatory Factors"],"mesh_terms":["Mice, Knockout, ApoE","Animals","Apolipoproteins E","Disease Models, Animal","Humans","Inflammation","Mice, Inbred C57BL","Stress, Mechanical","Mice, Knockout","Active Transport, Cell Nucleus","Nested Genes","Endothelial Cells","Atherosclerosis","Interferon Regulatory Factors","Mice","Gene Knockdown Techniques","Plaque, Atherosclerotic","Human Umbilical Vein Endothelial Cells"],"keywords":["Gene","Nested polymerase chain reaction","Gene flow","Cell biology","Biology","Genetics","Human","Atherosclerosis","Mouse","Shear stress","Medicine","endothelial cell activation","Irf5","Nested Gene"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"geo"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-08T04:27:50.871392Z","pmid":null,"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":[]}