Rac1 GTPase mediates atrial fibrillation via activation of NADPH oxidase

Aims: 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: Samples of the left atrial appendage were analyzed in 7 patients with sinus rhythm (SR) and 8 patients with AF matched for atrial diameter. Patients with AF showed increased atrial fibrosis. The left atria in AF were characterized by 4-fold upregulation of Rac1 total protein and membrane expression, marked increase of Rac1 activity and upregulation of NADPH oxidase activity.

To test whether Rac1 plays a causal role in the pathogenesis in AF, mice with cardiac-specific overexpression of V12Rac1 (RacET) were compared to wildtype (WT) and WT undergoing transaortic constriction (TAC). At age 16 months, RacET but not TAC exhibited atrial enlargement. 75% of RacET but no WT or TAC mice showed AF, despite greater LV hypertrophy in TAC. Treatment of RacET with rosuvastatin (0.4mg/d po, 10 months) did not alter weight or fibrosis of atria or ventricles but decreased cardiac Rac1- and NADPH oxidase activity and reduced the incidence of atrial fibrillation by 50%.

Conclusions: Left atria of patients with AF are characterized by upregulation of Rac1 and NADPH oxidase activity. Cardiac-specific overexpression 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.