Ce-452774-1 nox2 inhibition reduces af in diet-induced obese mice by reversing atrial remodeling caused by increased ros production

Diet induced obese (DIO) mice display both increased susceptibility to inducible atrial fibrillation (AF) and an overall increase in reactive oxygen species (ROS) production specific both to the cytosol and mitochondria. NADPH oxidase 2 (NOX2), a major source of cytosolic ROS production in human atria, has been implicated in ion channel remodeling leading to AF independent of obesity and is significantly increased in the atria of DIO mice. Although treatment with MitoTEMPO, a mitochondrial specific antioxidant (MitoTEMPO) 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. To test the hypothesis that increased NOX2 modulates atrial remodeling in obesity-induced AF, we used lean control mice, DIO and Nox2-KO mice fed with a 60% for a period of 10 weeks (DIO Nox2 -KO mice) and DIO mice treated with a NOX2 blocker, apocynin (DIO-Apocynin). Trans-esophageal rapid (TE) pacing and echocardiography were used to look at changes to AF phenotype and heart function. Cellular electrophysiology (EP), immunohistochemistry, Western blotting, whole-cell patch clamping and optical mapping studies were performed to study ion channel remodeling and increase in oxidative stress and ROS production. The average weight of control, DIO, DIO-Apocynin, and DIO Nox2 -KO mice were 31.70 ± 1.19 g, 38.18 ± 3.848 g, 43.96 ± 7.584 g, and 39.93 ± 4.99 g respectively. (Figure A) After TE pacing, DIO-Apocynin mice displayed 28.26 ± 25.40 s and DIO Nox2 -KO mice displayed 17.43 ± 31.80 s compared to 167.3 ± 168.9 s in DIO mice (Figure B). Whole cell patch clamping and electrical mapping studies show that Nox2 inhibition reverses ion channel remodeling (Figure E-F) and atrial fibrosis (Figure I-J) seen in DIO mice and prolongs the atrial AP (Figure C-D) and increases conduction velocity (CV) (Figure G-H) in the left atria. (Figure B) Also atrial cells from DIO Nox2-KO mice displayed increased expression of antioxidant protein SOD2 and reduced superoxide production. (Figure K-L) 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.