Abstract 15234: Targeted Inhibition of NADPH Oxidase in the Posterior Left Atrium by Nox2 shRNA Decreases Formation of Atrial Fibrillation Substrate in Heart Failure
Introduction: Oxidative stress is thought to play an important role in the pathogenesis of atrial fibrillation (AF). Recent studies indicate that NADPH oxidase (NOX2) is a major source of reactive oxygen species (ROS) in the fibrillating atrium. We hypothesized that targeted inhibition of NOX2 by shRNA will decrease formation of AF substrate e.g. interstitial fibrosis in a congestive heart failure (CHF) model of AF.
Methods: In 3 dogs, 5 mg of shRNA against NOX2 under the control of the RNA polymerase III promoter, U6, was injected sub-epicardially in the posterior left atrium (PLA) followed by electroporation to facilitate intracellular gene transfer. 7 dogs underwent injection of a control plasmid (pUBc-LacZ). All animals were then subjected to 3 weeks of ventricular tachypacing (to induce CHF). At 3 weeks, the following were assessed: AF by open-chest mapping. NOX2 expression by real time PCR. superoxide (O2-) production by lucigenin chemiluminscence assay and fibrosis by Masson’s trichrome staining.
Results: In NOX2 transfected PLA compared to controls: 1) NOX2 expression was decreased by 66 ± 17%, 2) NADPH stimulated superoxide (O2-) was 25% lower and 3) interstitial fibrosis was significantly decreased (Fig 1A). Most importantly, AF duration in NOX2 shRNA dogs was significantly decreased compared to controls (figure 1B).
Conclusions: In the setting of CHF, a reduction of O2- in the CHF PLA by gene based targeting of NOX2 prevents structural remodeling in the CHF atrium (resulting in a decrease in AF). Gene based targeting of ROS may have therapeutic potential in patients with AF.
- © 2013 by American Heart Association, Inc.