Modulation of NOX2 causes obesity-mediated atrial fibrillation
Arvind Sridhar, … , Jalees Rehman, Dawood Darbar
Arvind Sridhar, … , Jalees Rehman, Dawood Darbar
Published August 15, 2024
Citation Information: J Clin Invest. 2024;134(18):e175447. https://doi.org/10.1172/JCI175447.
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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.

Authors

Arvind Sridhar, Jaime DeSantiago, Hanna Chen, Mahmud Arif Pavel, Olivia Ly, Asia Owais, Miles Barney, Jordan Jousma, Sarath Babu Nukala, Khaled Abdelhady, Malek Massad, Lona Ernst Rizkallah, Sang-Ging Ong, Jalees Rehman, Dawood Darbar

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Figure 1

Genetic and pharmacological inhibition of NADPH oxidase 2 (NOX2) reduces obesity-mediated AF.

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Genetic and pharmacological inhibition of NADPH oxidase 2 (NOX2) reduces...
(A) Human NOX2 mRNA expression versus patient BMI (kg/m2). (B) Human NOX2 mRNA expression in lean (n = 6), overweight (n = 3), and obese individuals (n = 7). (C) Average weight (grams) of control, diet-induced obesity (DIO), DIO-apocynin, Nox2-knockout (KO), and DIO Nox2-KO mice over 10-week duration with an HFD. (D) Final weights (grams) of all 5 groups of mice after 10 weeks of HFD. (E) Atrial electrograms showing sinus rhythm at baseline (top), pacing-induced AF in DIO mice (middle), and sinus rhythm restoration in DIO mice (bottom). (F) Pacing-induced AF burden (duration, seconds) in control (n = 8), DIO (n = 9), DIO-apocynin (n = 7), Nox2-KO (n = 5), and DIO Nox2-KO (n = 7) mice. P > 0.05, *P < 0.05, **P < 0.01, by 2-tailed, unpaired Student’s t test.