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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Research Article Cardiology

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 2

DIO Nox2-KO mice display increased atrial action potential and abrogation of obesity-induced ion channel remodeling.

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DIO Nox2-KO mice display increased atrial action potential and abrogatio...
(A and B) Whole-cell patch clamping of atrial myocytes of DIO Nox2-KO mice showed increased prolongation of shortened action potential duration (APD) caused by obesity. Representative AP tracings in atrial myocytes in control (n = 6 cells, n = 4 mice), DIO (n = 6 cells, n = 4 mice), Nox2-KO (n = 6 cells, n = 3 mice), and DIO Nox2-KO mice (n = 6 cells, n = 3 mice). (C) Instantaneous rate of voltage change over time (dV/dTmax), an indicator of atrial conduction velocity (CV; n = 6 cells). (D) Measured APD at 90% repolarization (APD90; n = 6 cells). (E) Representative sodium current (INa) tracings from control, DIO, and DIO Nox2-KO mice showing increased currents in DIO Nox2-KO atrial myocytes (n = 6 atrial cells, n = 3 mice). (F) INa and voltage relationship (I-V curves) in control (n = 6), DIO (n = 6), and DIO Nox2-KO mice (n = 6). (G) Representative L-type calcium current (ICa,L) tracings from control, DIO, and DIO Nox2-KO mice showing increased currents in DIO Nox2-KO atrial myocytes (n = 4 cells, n = 3 mice). (H) ICa,L and voltage relationship (I-V curves) in control (n = 4), DIO (n = 4), Nox2-KO (n = 4), and DIO Nox2-KO mice (n = 4). (I) Slow delayed rectifier potassium current (IKs; treated with 1 μM HMR-1556) and voltage relationship (I-V curves) in control (n = 5 cells, n = 3 mice), DIO (n = 4 cells, n = 3 mice), Nox2-KO (n = 7 cells, n = 3 mice), and DIO Nox2-KO mice (n = 8 cells, 3 mice). (J) Comparison of IKs at 50 mV in control (n = 5 cells), DIO (n = 4 cells), Nox2-KO (n = 7 cells), and DIO Nox2-KO mice (n = 8 cells). P > 0.05, *P < 0.05, by 1-tailed ANOVA with Bonferroni’s post hoc test for multiple comparisons.