PRECLINICAL STUDY
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.
|
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 |
|
This article has been cited by other articles:
|
|
|
|
 
M. T. Elnakish, M. M. Awad, M. D. H. Hassona, M. A. Alhaj, A. Kulkarni, L. A. Citro, M. Sayyid, Z. A. Abouelnaga, O. El-Sayed, P. Kuppusamy, et al.
Cardiac remodeling caused by transgenic overexpression of a corn Rac gene
Am J Physiol Heart Circ Physiol,
September 1, 2011;
301(3):
H868 - H880.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y.-H. Yeh, C.-T. Kuo, T.-H. Chan, G.-J. Chang, X.-Y. Qi, F. Tsai, S. Nattel, and W.-J. Chen
Transforming growth factor-{beta} and oxidative stress mediate tachycardia-induced cellular remodelling in cultured atrial-derived myocytes
Cardiovasc Res,
July 1, 2011;
91(1):
62 - 70.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C.-T. Tsai, C.-D. Tseng, J.-J. Hwang, C.-K. Wu, C.-C. Yu, Y.-C. Wang, W.-P. Chen, L.-P. Lai, F.-T. Chiang, and J.-L. Lin
Tachycardia of atrial myocytes induces collagen expression in atrial fibroblasts through transforming growth factor {beta}1
Cardiovasc Res,
March 1, 2011;
89(4):
805 - 815.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Murthy, A. Ryan, C. He, R. K. Mallampalli, and A. B. Carter
Rac1-mediated Mitochondrial H2O2 Generation Regulates MMP-9 Gene Expression in Macrophages via Inhibition of SP-1 and AP-1
J. Biol. Chem.,
August 6, 2010;
285(32):
25062 - 25073.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-C. Reil, M. Hohl, M. Oberhofer, A. Kazakov, L. Kaestner, P. Mueller, O. Adam, C. Maack, P. Lipp, C. Mewis, et al.
Cardiac Rac1 overexpression in mice creates a substrate for atrial arrhythmias characterized by structural remodelling
Cardiovasc Res,
August 1, 2010;
87(3):
485 - 493.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Xiao, D. Liang, H. Zhao, Y. Liu, H. Zhang, X. Lu, Y. Liu, J. Li, L. Peng, and Y.-H. Chen
2-Aminoethoxydiphenyl borate, a inositol 1,4,5-triphosphate receptor inhibitor, prevents atrial fibrillation
Exp Biol Med,
July 1, 2010;
235(7):
862 - 868.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Santangeli, G. Ferrante, G. Pelargonio, A. Dello Russo, M. Casella, S. Bartoletti, L. Di Biase, F. Crea, and A. Natale
Usefulness of statins in preventing atrial fibrillation in patients with permanent pacemaker: a systematic review
Europace,
May 1, 2010;
12(5):
649 - 654.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. Adam, D. Lavall, K. Theobald, M. Hohl, M. Grube, S. Ameling, M. A. Sussman, S. Rosenkranz, H. K. Kroemer, H.-J. Schafers, et al.
Rac1-Induced Connective Tissue Growth Factor Regulates Connexin 43 and N-Cadherin Expression in Atrial Fibrillation
J. Am. Coll. Cardiol.,
February 2, 2010;
55(5):
469 - 480.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. K. Liao
Rac1 and Connective Tissue Growth Factor: The Missing Link Between Atrial Remodeling and the Pathogenesis of Atrial Fibrillation?
J. Am. Coll. Cardiol.,
February 2, 2010;
55(5):
481 - 482.
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Nishida, G. Michael, D. Dobrev, and S. Nattel
Animal models for atrial fibrillation: clinical insights and scientific opportunities
Europace,
February 1, 2010;
12(2):
160 - 172.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Murthy, A. Adamcakova-Dodd, S. S. Perry, L. A. Tephly, R. M. Keller, N. Metwali, D. K. Meyerholz, Y. Wang, M. Glogauer, P. S. Thorne, et al.
Modulation of reactive oxygen species by Rac1 or catalase prevents asbestos-induced pulmonary fibrosis
Am J Physiol Lung Cell Mol Physiol,
November 1, 2009;
297(5):
L846 - L855.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Prinz and M. Endres
The Acute (Cerebro)Vascular Effects of Statins
Anesth. Analg.,
August 1, 2009;
109(2):
572 - 584.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. J. Camm, P. Kirchhof, G. Y.H. Lip, I. Savelieva, and S. Ernst
CHAPTER 29 Atrial Fibrillation
ESC Textbook of Cardiovascular Medicine,
January 1, 2009;
2(1):
med-9780199566990-chapter - med-9780199566990-chapter.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. J. Stuck, M. Lenski, M. Bohm, and U. Laufs
Metabolic Switch and Hypertrophy of Cardiomyocytes following Treatment with Angiotensin II Are Prevented by AMP-activated Protein Kinase
J. Biol. Chem.,
November 21, 2008;
283(47):
32562 - 32569.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Sanchez-Quinones, F. Marin, V. Roldan, and G.Y.H. Lip
The impact of statin use on atrial fibrillation
QJM,
November 1, 2008;
101(11):
845 - 861.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. Adam, H.-R. Neuberger, M. Bohm, and U. Laufs
Prevention of Atrial Fibrillation With 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors
Circulation,
September 16, 2008;
118(12):
1285 - 1293.
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Ogata, T. Ueyama, K. Isodono, M. Tagawa, N. Takehara, T. Kawashima, K. Harada, T. Takahashi, T. Shioi, H. Matsubara, et al.
MURC, a Muscle-Restricted Coiled-Coil Protein That Modulates the Rho/ROCK Pathway, Induces Cardiac Dysfunction and Conduction Disturbance
Mol. Cell. Biol.,
May 15, 2008;
28(10):
3424 - 3436.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Nattel, B. Burstein, and D. Dobrev
Atrial Remodeling and Atrial Fibrillation: Mechanisms and Implications
Circ Arrhythm Electrophysiol,
April 1, 2008;
1(1):
62 - 73.
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Ozaydin, O. Peker, D. Erdogan, S. Kapan, Y. Turker, E. Varol, F. Ozguner, A. Dogan, and E. Ibrisim
N-acetylcysteine for the prevention of postoperative atrial fibrillation: a prospective, randomized, placebo-controlled pilot study
Eur. Heart J.,
March 1, 2008;
29(5):
625 - 631.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Ramasubbu, J. Estep, D. L. White, A. Deswal, and D. L. Mann
Experimental and Clinical Basis for the Use of Statins in Patients With Ischemic and Nonischemic Cardiomyopathy
J. Am. Coll. Cardiol.,
January 29, 2008;
51(4):
415 - 426.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Marcoff and P. D. Thompson
Reply
J. Am. Coll. Cardiol.,
November 6, 2007;
50(19):
1911 - 1911.
[Full Text]
[PDF]
|
|
|
|
