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.
View: Text | PDF
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

×

Figure 5

NOX2 inhibition prevents atrial fibrosis and increases atrial CV in DIO mice.

Options: View larger image (or click on image) Download as PowerPoint
NOX2 inhibition prevents atrial fibrosis and increases atrial CV in DIO ...
(A) Representative isochronal maps of the LA in the 3 groups of mice using electrical mapping. (B) Quantification of mean LA CV in control (n = 6), DIO (n = 6), Nox2-KO (n = 5), and DIO Nox2-KO mice (n = 6). (C) Representative isochronal maps of the RA in the 3 groups of mice using electrical mapping. (D) Quantification of mean RA CV in control (n = 6), DIO (n = 6), Nox2-KO (n = 5), and DIO Nox2-KO mice (n = 6). (E) Picrosirius red staining of atrial myocytes from control, DIO, Nox2-KO, and DIO Nox2-KO. (F) Change in fibrosis (%) in the 3 groups of mice showing a significant reduction in fibrosis in DIO Nox2-KO compared with DIO mice (n = 3 mice each). Scale bar: 50 μm. (G) Masson’s trichrome staining of atrial myocytes from control, DIO, and DIO Nox2-KO. Scale bar: 50 μm. (H) Change in fibrosis (%) in the 4 groups of mice showing a significant reduction in fibrosis in DIO Nox2-KO compared with DIO mice (n = 3 mice each). *P < 0.05, **P < 0.01, by 2-tailed, unpaired Student’s t test.