Abstract 1253: Rac1 GTPase Mediates Atrial Fibrillation
Introduction: The signal transduction leading to atrial fibrillation (AF) is incompletely understood. We hypothesized that activation of Rac1 GTPase contributes to the pathogenesis of AF via activation of NADPH oxidase and production of reactive oxygen species.
Methods and Results: Tissue samples of the left atrial appendage of patients undergoing mitral valve surgery were analyzed in 8 patients with sinus rhythm (SR) and 8 patients with AF matched for atrial diameter and medication. Patients on statins were excluded. Collagen content was 8.5±1.3% in the left atrium in SR compared to 14.9±2.1% in AF. Western blot analysis showed upregulation of Rac1 total protein to 361±47% and Rac1 membrane expression to 428±146% in AF vs. SR patients. In AF, Rac1 activity (PAK pull-down assays) was increased to 362±98%. This was associated with a 20-fold upregulation of NADPH oxidase activity in AF vs SR (2225±500%). In order to test whether Rac1 plays a causal role in the pathogenesis in AF, n=10 transgenic mice with cardiac overexpression (αMHC promoter) of Rac1 (RacET) were compared to wildtype (WT) and WT undergoing transaortic constriction (TAC, 360 μm). After 16 month, echocardiography showed similar left ventricular hypertrophy in RacET and TAC. RacET but not TAC exhibited atrial enlargement; 75% of RacET but no WT or TAC showed AF. At the age of 10 months, RacET had only slightly enlarged atria compared to WT. Treatment of RacET with rosuvastatin (0.4 mg/d po, 10 mo, n=10 per group) did not alter the weight of atria or ventricles but decreased cardiac Rac1-activity to 77±3.3%, inhibited NADPH oxidase activity and reduced the incidence of atrial fibrillation (20% AF in RacET+statin vs. 44% AF in RacET). All effects are significant with p<0.05.
Conclusion: Left atria of patients with AF are characterized by upregulation of Rac1 and NADPH oxidase activity. Cardiac-specific overex-pression of Rac1 in mice causes AF independent of left ventricular hypertrophy, which can be reduced by statin-mediated inhibition of Rac1. Rac1-mediated activation of left atrial NADPH-oxidase may represent a novel target for the prevention of atrial fibrillation.