title: Rac1-induced connective tissue growth factor regulates connexin 43 and N-cadherin expression in atrial fibrillation.
abstract: OBJECTIVE
  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.
authors.affiliation: Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarland, Homburg/Saar, Germany. oliver.adam@uks.eu
authors.forename: Oliver
authors.initials: O
authors.lastname: Adam
authors.forename: Daniel
authors.initials: D
authors.lastname: Lavall
authors.forename: Katharina
authors.initials: K
authors.lastname: Theobald
authors.forename: Mathias
authors.initials: M
authors.lastname: Hohl
authors.forename: Markus
authors.initials: M
authors.lastname: Grube
authors.forename: Sabine
authors.initials: S
authors.lastname: Ameling
authors.forename: Mark A
authors.initials: MA
authors.lastname: Sussman
authors.forename: Stephan
authors.initials: S
authors.lastname: Rosenkranz
authors.forename: Heyo K
authors.initials: HK
authors.lastname: Kroemer
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Schäfers
authors.forename: Michael
authors.initials: M
authors.lastname: Böhm
authors.forename: Ulrich
authors.initials: U
authors.lastname: Laufs
mesh_terms: D000368:Aged; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001281:Atrial Fibrillation / Q000378:metabolism* / Q000473:pathology; D015820:Cadherins / Q000378:metabolism*; D055513:Connective Tissue Growth Factor / Q000378:metabolism*; D018031:Connexin 43 / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis; D020869:Gene Expression Profiling; D006325:Heart Atria / Q000378:metabolism / Q000473:pathology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020239:Receptor Cross-Talk; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: C526317:CCN2 protein, human; D015820:Cadherins; D018031:Connexin 43; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C107953:RAC1 protein, human; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; C066737:RHOA protein, human; D055513:Connective Tissue Growth Factor; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein