Modulation of NOX2 causes obesity-mediated atrial fibrillation

• Published in: The Journal of clinical investigation 2024-09, Vol.134 (18), p.1-19
• Main Authors: Sridhar, Arvind, DeSantiago, Jaime, Chen, Hanna, Pavel, Mahmud Arif, Ly, Olivia, Owais, Asia, Barney, Miles, Jousma, Jordan, Nukala, Sarath Babu, Abdelhady, Khaled, Massad, Malek, Rizkallah, Lona Ernst, Ong, Sang-Ging, Rehman, Jalees, Darbar, Dawood
• Format: Article
• Language: English
• Subjects: Action potential; Animals; Atrial fibrillation; Atrial Fibrillation - enzymology; Atrial Fibrillation - etiology; Atrial Fibrillation - genetics; Atrial Fibrillation - metabolism; Atrial Fibrillation - pathology; Atrial Remodeling; Body mass index; Cardiac arrhythmia; Cardiomyocytes; Cardiovascular disease; CYBB protein; Fatty acids; Fibrillation; Heart failure; Homeobox; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Hydrogen peroxide; Induced Pluripotent Stem Cells - metabolism; Kinases; Male; Mice; Mice, Knockout; Myocytes, Cardiac - enzymology; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; NAD(P)H oxidase; NADPH Oxidase 2 - genetics; NADPH Oxidase 2 - metabolism; Obesity; Obesity - genetics; Obesity - metabolism; Obesity - pathology; Overweight; Oxidases; Oxidative Stress; Palmitic acid; Pathophysiology; Pluripotency; Reactive oxygen species; Reactive Oxygen Species - metabolism; Scientific equipment and supplies industry; Stem cells; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Transcriptomics
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI175447

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.