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ResearchIn-Press PreviewCardiology Open Access | 10.1172/JCI175447
1Division of Cardiology, University of Illinois Chicago, Chicago, United States of America
2Department of Pharmacology, University of Illinois Chicago, Chicago, United States of America
3Division of Cardiothoracic Surgery, University of Illinois Chicago, Chicago, United States of America
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1Division of Cardiology, University of Illinois Chicago, Chicago, United States of America
2Department of Pharmacology, University of Illinois Chicago, Chicago, United States of America
3Division of Cardiothoracic Surgery, University of Illinois Chicago, Chicago, United States of America
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1Division of Cardiology, University of Illinois Chicago, Chicago, United States of America
2Department of Pharmacology, University of Illinois Chicago, Chicago, United States of America
3Division of Cardiothoracic Surgery, University of Illinois Chicago, Chicago, United States of America
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1Division of Cardiology, University of Illinois Chicago, Chicago, United States of America
2Department of Pharmacology, University of Illinois Chicago, Chicago, United States of America
3Division of Cardiothoracic Surgery, University of Illinois Chicago, Chicago, United States of America
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1Division of Cardiology, University of Illinois Chicago, Chicago, United States of America
2Department of Pharmacology, University of Illinois Chicago, Chicago, United States of America
3Division of Cardiothoracic Surgery, University of Illinois Chicago, Chicago, United States of America
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1Division of Cardiology, University of Illinois Chicago, Chicago, United States of America
2Department of Pharmacology, University of Illinois Chicago, Chicago, United States of America
3Division of Cardiothoracic Surgery, University of Illinois Chicago, Chicago, United States of America
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1Division of Cardiology, University of Illinois Chicago, Chicago, United States of America
2Department of Pharmacology, University of Illinois Chicago, Chicago, United States of America
3Division of Cardiothoracic Surgery, University of Illinois Chicago, Chicago, United States of America
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1Division of Cardiology, University of Illinois Chicago, Chicago, United States of America
2Department of Pharmacology, University of Illinois Chicago, Chicago, United States of America
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1Division of Cardiology, University of Illinois Chicago, Chicago, United States of America
2Department of Pharmacology, University of Illinois Chicago, Chicago, United States of America
3Division of Cardiothoracic Surgery, University of Illinois Chicago, Chicago, United States of America
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1Division of Cardiology, University of Illinois Chicago, Chicago, United States of America
2Department of Pharmacology, University of Illinois Chicago, Chicago, United States of America
3Division of Cardiothoracic Surgery, University of Illinois Chicago, Chicago, United States of America
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1Division of Cardiology, University of Illinois Chicago, Chicago, United States of America
2Department of Pharmacology, University of Illinois Chicago, Chicago, United States of America
3Division of Cardiothoracic Surgery, University of Illinois Chicago, Chicago, United States of America
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1Division of Cardiology, University of Illinois Chicago, Chicago, United States of America
2Department of Pharmacology, University of Illinois Chicago, Chicago, United States of America
3Division of Cardiothoracic Surgery, University of Illinois Chicago, Chicago, United States of America
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1Division of Cardiology, University of Illinois Chicago, Chicago, United States of America
2Department of Pharmacology, University of Illinois Chicago, Chicago, United States of America
3Division of Cardiothoracic Surgery, University of Illinois Chicago, Chicago, United States of America
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1Division of Cardiology, University of Illinois Chicago, Chicago, United States of America
2Department of Pharmacology, University of Illinois Chicago, Chicago, United States of America
3Division of Cardiothoracic Surgery, University of Illinois Chicago, Chicago, United States of America
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1Division of Cardiology, University of Illinois Chicago, Chicago, United States of America
2Department of Pharmacology, University of Illinois Chicago, Chicago, United States of America
3Division of Cardiothoracic Surgery, University of Illinois Chicago, Chicago, United States of America
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Published August 15, 2024 - More info
Obesity is linked to an increased risk of atrial fibrillation (AF) via increased oxidative stress. While NADPH oxidase II (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-knock-out (KO) 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.