{"doi":"10.1172/jci175447","title":"Modulation of NOX2 causes obesity-mediated atrial fibrillation","abstract":"Obesity is linked to an increased risk of atrial fibrillation (AF) via increased oxidative stress. While NADPH oxidase 2 (NOX2), a major source of oxidative stress and reactive oxygen species (ROS) in the heart, predisposes to AF, the underlying mechanisms remain unclear. Here, we studied NOX2-mediated ROS production in obesity-mediated AF using Nox2-knockout mice and mature human induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCMs). Diet-induced obesity (DIO) mice and hiPSC-aCMs treated with palmitic acid (PA) were infused with a NOX blocker (apocynin) and a NOX2-specific inhibitor, respectively. We showed that NOX2 inhibition normalized atrial action potential duration and abrogated obesity-mediated ion channel remodeling with reduced AF burden. Unbiased transcriptomics analysis revealed that NOX2 mediates atrial remodeling in obesity-mediated AF in DIO mice, PA-treated hiPSC-aCMs, and human atrial tissue from obese individuals by upregulation of paired-like homeodomain transcription factor 2 (PITX2). Furthermore, hiPSC-aCMs treated with hydrogen peroxide, a NOX2 surrogate, displayed increased PITX2 expression, establishing a mechanistic link between increased NOX2-mediated ROS production and modulation of PITX2. Our findings offer insights into possible mechanisms through which obesity triggers AF and support NOX2 inhibition as a potential novel prophylactic or adjunctive therapy for patients with obesity-mediated AF.","journal":"Journal of Clinical Investigation","year":2024,"id":425654,"datarank":0.5717897172844875,"base_score":2.995732273553991,"endowment":2.995732273553991,"self_citation_contribution":0.4493598410330987,"citation_network_contribution":0.12242987625138874,"self_endowment_contribution":0.4493598410330987,"citer_contribution":0.12242987625138874,"corpus_percentile":null,"corpus_rank":null,"citation_count":19,"citer_count":17,"citers_with_citation_signal":10,"citers_with_endowment":10,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9642,"is_data_producer":true,"deposit_databanks":{"GEO":["GSE271748"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":330442,"name":"Jaime DeSantiago","orcid":null,"position":1,"is_corresponding":false},{"id":664210,"name":"Hanna Chen","orcid":null,"position":2,"is_corresponding":false},{"id":245304,"name":"Mahmud Arif Pavel","orcid":"0000-0002-2709-8744","position":3,"is_corresponding":false},{"id":663525,"name":"Olivia T Ly","orcid":"0000-0002-9658-9643","position":4,"is_corresponding":false},{"id":1223826,"name":"Asia Owais","orcid":"0000-0003-3401-7866","position":5,"is_corresponding":false},{"id":1223827,"name":"Miles Barney","orcid":"0000-0002-1066-9635","position":6,"is_corresponding":false},{"id":295227,"name":"Jordan Jousma","orcid":"0000-0001-5434-2573","position":7,"is_corresponding":false},{"id":295225,"name":"Sarath Babu Nukala","orcid":"0000-0002-0216-7168","position":8,"is_corresponding":false},{"id":872194,"name":"Khaled Abdelhady","orcid":"0000-0002-5938-6986","position":9,"is_corresponding":false},{"id":868090,"name":"Malek G. Massad","orcid":null,"position":10,"is_corresponding":false},{"id":873039,"name":"Lona Ernst Rizkallah","orcid":null,"position":11,"is_corresponding":false},{"id":259482,"name":"Sang‐Ging Ong","orcid":"0000-0003-0182-8769","position":12,"is_corresponding":false},{"id":235204,"name":"Jalees Rehman","orcid":"0000-0002-2787-9292","position":13,"is_corresponding":false},{"id":1049,"name":"Dawood Darbar","orcid":"0000-0002-4103-5977","position":14,"is_corresponding":false},{"id":663526,"name":"Arvind Sridhar","orcid":"0000-0003-4754-7719","position":0,"is_corresponding":true}],"reference_count":74,"raw_metadata":null,"created_at":"2026-07-19T01:58:32.160975Z","pmid":"39146015","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":[]}