Role of Rac1 GTPase activation in atrial fibrillation.
OBJECTIVE
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.
Adam
Oliver
O
Klinik für Innere Medizin III, Kardiologie, Angiologie und internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany.
Frost
Gregg
G
Custodis
Florian
F
Sussman
Mark A
MA
Schäfers
Hans-Joachim
HJ
Böhm
Michael
M
Laufs
Ulrich
U
D000368:Aged; D000818:Animals; D001281:Atrial Fibrillation / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005260:Female; D005464:Fluorobenzenes / Q000627:therapeutic use; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D006325:Heart Atria / Q000378:metabolism / Q000473:pathology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019255:NADPH Oxidases / Q000378:metabolism; D011743:Pyrimidines / Q000627:therapeutic use; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000627:therapeutic use; D015854:Up-Regulation; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D003094:Collagen; D019255:NADPH Oxidases; D020558:GTP Phosphohydrolases; D020830:rac1 GTP-Binding Protein