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

• Published in: Journal of the American College of Cardiology 2010-02, Vol.55 (5), p.469-480
• Main Authors: Adam, Oliver, MD, Lavall, Daniel, MS, Theobald, Katharina, MS, Hohl, Mathias, PhD, Grube, Markus, PhD, Ameling, Sabine, MS, Sussman, Mark A., PhD, Rosenkranz, Stephan, MD, PhD, Kroemer, Heyo K., PhD, Schäfers, Hans-Joachim, MD, Böhm, Michael, MD, Laufs, Ulrich, MD
• Format: Article
• Language: English
• Subjects: Aged; Agreements; Angiotensin II - metabolism; Animals; Animals, Newborn; Arrays; atrial fibrillation; Atrial Fibrillation - metabolism; Atrial Fibrillation - pathology; Biological and medical sciences; Biotechnology; Cadherins - metabolism; Cardiac arrhythmia; Cardiac dysrhythmias; Cardiology; Cardiology. Vascular system; Cardiomyocytes; Cardiovascular; Cell culture; Connective Tissue Growth Factor - metabolism; connexin 43; Connexin 43 - metabolism; CTGF; Deoxyribonucleic acid; DNA; Experiments; Female; Fibroblasts - metabolism; Fibrosis; Gene Expression Profiling; Heart; Heart Atria - metabolism; Heart Atria - pathology; Humans; Hybridization; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Internal Medicine; Laboratory animals; Male; Medical sciences; Mice; Mice, Transgenic; Middle Aged; Myocardium - metabolism; Myocardium - pathology; Myocytes, Cardiac - metabolism; Oxidative stress; Rac1; rac1 GTP-Binding Protein - metabolism; Rats; Rats, Sprague-Dawley; Receptor Cross-Talk; rhoA GTP-Binding Protein - metabolism; RNA polymerase; Rodents; Signal Transduction; Software; Statins; Studies; Transforming Growth Factor beta1 - metabolism; Transgenic animals
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2009.08.064

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.