PRECLINICAL STUDIES
Role of Rac1 GTPase Activation in Atrial Fibrillation
Oliver Adam, MD*,
Gregg Frost*,
Florian Custodis, MD*,
Mark A. Sussman, PhD ,
Hans-Joachim Schäfers, MD ,
Michael Böhm, MD* and
Ulrich Laufs, MD*,*
* Klinik für Innere Medizin III, Kardiologie, Angiologie und internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany
Abteilung für Thorax- und Herz- Gefäßchirurgie, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany
San Diego State University, SDSU Heart Institute and Department of Biology, San Diego, California
Manuscript received January 9, 2007;
revised manuscript received February 15, 2007,
accepted March 5, 2007.
* Reprint requests and correspondence: Dr. Ulrich Laufs, Klinik für Innere Medizin III Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, 66424 Homburg/Saar, Germany. (Email: ulrich{at}laufs.com).
Objectives: We aimed to study the role of Rac1 GTPase in atrial fibrillation (AF).
Background: The signal transduction associated with AF is incompletely understood. We hypothesized that activation of Rac1 GTPase contributes to the pathogenesis of AF via activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and production of reactive oxygen species.
Methods: Old mice with cardiac-specific overexpression of constitutively active V12Rac1 (RacET) were compared with wild-type (WT) and WT undergoing transaortic constriction (TAC). In addition, samples of human left atrial appendages were analyzed in patients with sinus rhythm (SR) compared with patients with permanent AF matched for atrial diameter.
Results: At age 16 months, 75% of RacET but no WT or TAC mice showed AF. Treatment of RacET with statins for 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 AF by 50%. The left atria of patients with AF showed increased fibrosis, up-regulation of NADPH oxidase activity, a 4-fold increase of Rac1 total protein and membrane expression as well as up-regulation of Rac1 activity.
Conclusions: Chronic cardiac overexpression of Rac1 represents a novel mouse model for AF. Rac1 GTPase contributes to the pathogenesis of AF and identifies a target for the prevention and treatment of AF.
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Abbreviations and Acronyms
| | AF = atrial fibrillation | | ECG = electrocardiography | | LA = left atrium | | LV = left ventricle | | NADPH = nicotinamide adenine dinucleotide phosphate | | RacET = transgenic mice with cardiac overexpression of Rac1 GTPase | | SR = sinus rhythm | | TAC = transverse aortic constriction | | WT = wild-type mice |
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