Abstract 14496: NOX2 Inhibition Reverses Atrial Remodeling Caused by Increased Oxidative Stress and Reduces AF in Diet Induced Obese Mice

Abstract

Introduction: Diet induced obese (DIO) mice display increased inducible atrial fibrillation (AF) and an overall increase in reactive oxygen species (ROS) production. NADPH oxidase 2 (NOX2), a major source of cytosolic ROS production in human atria, has been implicated in AF independent of obesity and is significantly increased in the atria of DIO mice. Although treatment with MitoTEMPO, a mitochondrial specific antioxidant reduced AF burden in DIO mice, the actual role of NOX2 in increasing ROS production and atrial remodeling in the context of obesity-induced AF remains unclear. Hypothesis: To test the hypothesis that increased NOX2 modulates atrial remodeling in obesity-induced AF, we used control mice, DIO and Nox2 -KO mice fed with a 60% HFD for 10 weeks (DIO-KO) and DIO mice treated with a NOX2 blocker, apocynin (DIO-Apocynin). Methods: Trans-esophageal rapid (TE) pacing was used to look at the AF phenotype. Cellular electrophysiology (EP), Western blotting, whole-cell patch clamping were performed to study ion channel remodeling and ROS production. Results: All three DIO mouse groups displayed significantly greater body weight compared to their respective controls (Figure A) After TE pacing, DIO-Apocynin mice displayed 28.26 ± 25.40 s and DIO-KO mice displayed 17.43 ± 31.80 s compared to 167.3 ± 168.9 s in DIO mice (Figure B). NOX2 inhibition reversed obesity-induced ion channel remodeling of potassium channels such as KCNQ1 and KCNE1 encoding for the IKs current and KCNA5 encoding for the IKur current and also reduced mediators of oxidative stress. (Figure C-M) Lastly, voltage clamp in DIO-KO mice showed that NOX2 inhibition reverses obesity-induced IK current increase. (Figure N-O) Conclusions: Thus, these results prove that antioxidant therapy targeting Nox2 abrogated ion channel remodeling and reversed the obesity-induced AF burden. Our findings show the importance of targeting specific antioxidant pathways to manage the AF in patients with obesity.