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Modulation of NOX2 causes obesity-mediated atrial fibrillation
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Modulation of NOX2 causes obesity-mediated atrial fibrillation
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Journal Article
Modulation of NOX2 causes obesity-mediated atrial fibrillation
2024
Overview
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.
Publisher
American Society for Clinical Investigation
Subject
/ Animals
/ Atrial Fibrillation - enzymology
/ Atrial Fibrillation - etiology
/ Atrial Fibrillation - genetics
/ Atrial Fibrillation - metabolism
/ Atrial Fibrillation - pathology
/ Complications and side effects
/ Homeobox
/ Homeodomain Proteins - genetics
/ Homeodomain Proteins - metabolism
/ Humans
/ Induced Pluripotent Stem Cells - metabolism
/ Kinases
/ Male
/ Mice
/ Myocytes, Cardiac - enzymology
/ Myocytes, Cardiac - metabolism
/ Myocytes, Cardiac - pathology
/ NADPH Oxidase 2 - metabolism
/ Obesity
/ Oxidases
/ Reactive Oxygen Species - metabolism
/ Scientific equipment and supplies industry
/ Transcription Factors - genetics
