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PRE-CLINICAL RESEARCH

Rac1-Induced Connective Tissue Growth Factor Regulates Connexin 43 and N-Cadherin Expression in Atrial Fibrillation

Oliver Adam, MD^_*,_*, Daniel Lavall, MS^_*, Katharina Theobald, MS^_*, Mathias Hohl, PhD^_*, Markus Grube, PhD, Sabine Ameling, MS, Mark A. Sussman, PhD^||, Stephan Rosenkranz, MD, PhD^¶, Heyo K. Kroemer, PhD, Hans-Joachim Schäfers, MD, Michael Böhm, MD^_* and Ulrich Laufs, MD^_*

^_* Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarland, Homburg/Saar, Germany
Klinik für Thorax- und Herz-Gefässchirurgie, Universitätsklinikum des Saarland, Homburg/Saar, Germany
Department of Pharmacology, Ernst Moritz Arndt University, Greifswald, Germany
Department of Functional Genomics, Ernst Moritz Arndt University, Greifswald, Germany
^|| SDSU Heart Institute and Department of Biology, San Diego State University, San Diego, California
^¶ Klinik III für Innere Medizin, Kardiologie, Pneumonologie, Angiologie und Internistische Intensivmedizin, Universität zu Köln, Köln, Germany

Manuscript received March 10, 2009; revised manuscript received August 7, 2009, accepted August 10, 2009.

^_* Reprint requests and correspondence: Dr. Oliver Adam, Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Kirrbergerstr., Homburg/Saar 66424, Germany (Email: oliver.adam{at}uks.eu).

Objectives: We studied the signal transduction of atrial structural remodeling that contributes to the pathogenesis of atrial fibrillation (AF).

Background: Fibrosis is a hallmark of arrhythmogenic structural remodeling, but the underlying molecular mechanisms are incompletely understood.

Methods: We performed transcriptional profiling of left atrial myocardium from patients with AF and sinus rhythm and applied cultured primary cardiac cells and transgenic mice with overexpression of constitutively active V12Rac1 (RacET) in which AF develops at old age to characterize mediators of the signal transduction of atrial remodeling.

Results: Left atrial myocardium from patients with AF showed a marked up-regulation of connective tissue growth factor (CTGF) expression compared with sinus rhythm patients. This was associated with increased fibrosis, nicotinamide adenine dinucleotide phosphate oxidase, Rac1 and RhoA activity, up-regulation of N-cadherin and connexin 43 (Cx43) expression, and increased angiotensin II tissue concentration. In neonatal rat cardiomyocytes and fibroblasts, a specific small molecule inhibitor of Rac1 or simvastatin completely prevented the angiotensin II–induced up-regulation of CTGF, Cx43, and N-cadherin expression. Transfection with small-inhibiting CTGF ribonucleic acid blocked Cx43 and N-cadherin expression. RacET mice showed up-regulation of CTGF, Cx43, and N-cadherin protein expression. Inhibition of Rac1 by oral statin treatment prevented these effects, identifying Rac1 as a key regulator of CTGF in vivo.

Conclusions: The data identify CTGF as an important mediator of atrial structural remodeling during AF. Angiotensin II activates CTGF via activation of Rac1 and nicotinamide adenine dinucleotide phosphate oxidase, leading to up-regulation of Cx43, N-cadherin, and interstitial fibrosis and therefore contributing to the signal transduction of atrial structural remodeling.

Key Words: atrial fibrillation • Rac1 • CTGF • oxidative stress • connexin 43

Abbreviations and Acronyms   AF = atrial fibrillation   CTGF = connective tissue growth factor   Cx = connexin   ECG = electrocardiography   GTPase = guanosine triphosphatase   HMG-CoA = 3-hydroxy-3-methylglutaryl-coenzyme A   LA = left atrium   NADPH = nicotinamide adenine dinucleotide phosphate   np-Cx43 = nonphosphorylated connexin 43   qRT-PCR = quantitative real-time polymerase chain reaction   RacET = transgenic mice with cardiac-specific overexpression of a constitutively active Rac1   RNA = ribonucleic acid   siRNA = small interfering ribonucleic acid   SR = sinus rhythm   TGF = transforming growth factor   WT = wild-type

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