{"doi":"10.7554/elife.58064","title":"Methotrexate attenuates vascular inflammation through an adenosine-microRNA-dependent pathway","abstract":"Endothelial cell (EC) activation is an early hallmark in the pathogenesis of chronic vascular diseases. MicroRNA-181b ( Mir181b ) is an important anti-inflammatory mediator in the vascular endothelium affecting endotoxemia, atherosclerosis, and insulin resistance. Herein, we identify that the drug methotrexate (MTX) and its downstream metabolite adenosine exert anti-inflammatory effects in the vascular endothelium by targeting and activating Mir181b expression. Both systemic and endothelial-specific Mir181a2b2 -deficient mice develop vascular inflammation, white adipose tissue (WAT) inflammation, and insulin resistance in a diet-induced obesity model. Moreover, MTX attenuated diet-induced WAT inflammation, insulin resistance, and EC activation in a Mir181a2b2 -dependent manner. Mechanistically, MTX attenuated cytokine-induced EC activation through a unique adenosine-adenosine receptor A3-SMAD3/4- Mir181b signaling cascade. These findings establish an essential role of endothelial Mir181b in controlling vascular inflammation and that restoring Mir181b in ECs by high-dose MTX or adenosine signaling may provide a potential therapeutic opportunity for anti-inflammatory therapy.","journal":"eLife","year":2021,"id":170558,"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":27,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9561,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":251589,"name":"Stefan Haemmig","orcid":"0000-0001-5014-4393","position":1,"is_corresponding":false},{"id":251588,"name":"Haoyang Zhou","orcid":"0009-0000-9663-5016","position":2,"is_corresponding":false},{"id":251592,"name":"Daniel Pérez‐Cremades","orcid":"0000-0002-0969-8762","position":3,"is_corresponding":false},{"id":263718,"name":"Xinghui Sun","orcid":"0000-0002-1156-0375","position":4,"is_corresponding":false},{"id":263721,"name":"Lei Chen","orcid":"0000-0002-9327-1621","position":5,"is_corresponding":false},{"id":305754,"name":"Dafeng Yang","orcid":"0000-0003-2663-731X","position":6,"is_corresponding":false},{"id":704205,"name":"Jorge Haneo-Mejia","orcid":null,"position":7,"is_corresponding":false},{"id":263725,"name":"Tianlun Yang","orcid":"0000-0001-9835-1279","position":8,"is_corresponding":false},{"id":703461,"name":"Ivana Hollan","orcid":"0000-0001-6939-7534","position":9,"is_corresponding":false},{"id":251597,"name":"Mark W. Feinberg","orcid":"0000-0001-9523-3859","position":10,"is_corresponding":false},{"id":263717,"name":"Dafeng Yang","orcid":"0000-0002-8320-8215","position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":null,"created_at":"2026-07-18T23:46:24.040760Z","pmid":"33416495","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":[]}