title: Increased lysyl oxidase expression and collagen cross-linking during atrial fibrillation.
abstract: The aim of the study is to characterize the signal transduction leading to interstitial fibrosis in the pathogenesis of atrial fibrillation (AF) and atrial remodeling. Samples of the left atrial appendage (LA) from patients with AF showed higher collagen content (73 ± 5 vs. 38 ± 2 μg/mg protein) and 2.5-fold increased collagen crosslinking compared to patients with sinus rhythm (SR). Affymetrix-assays, RT-PCR and western Blot analysis revealed that LA of AF patients are characterized by increased lysyl oxidase (LOX) mRNA (218 ± 42%) and protein (253 ± 11%) expression. This was associated with increased expression of connective tissue growth factor (CTGF), fibronectin and Rac1 activity compared to SR. In neonatal cardiac fibroblasts, the Rac1 specific small molecule inhibitor NSC23766 prevented angiotensin II (AngII) induced upregulation of LOX (214 ± 16%) expression. Inhibition of CTGF by siRNA transfections completely inhibited AngII induced LOX expression. The LOX specific small molecule inhibitor BAPN prevented AngII and CTGF induced fibronectin expression. Left atria of transgenic mice with cardiac overexpression of Rac1 (RacET) that develop AF at high age exhibited upregulation of CTGF as well as LOX (187 ± 7%) and fibronectin (627 ± 146%) expression. Atria of RacET showed increased collagen content (28 ± 2 μg/mg protein) and crosslinking (10 ± 0.7) compared to wildtypes (20 ± 0.4 μg/mg protein; 5 ± 0.9). Left atrial myocardium of patients with atrial fibrillation is characterized by increased lysyl oxidase and fibronectin expression as well as collagen cross-linking. In cardiac fibroblasts, Rac1 GTPase mediates upregulation of fibronectin via LOX and CTGF. Inhibition of this signaling pathway may therefore represent a target for the prevention of fibrotic atrial remodeling.
authors.affiliation: Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany. oliver.adam@uks.eu
authors.forename: Oliver
authors.initials: O
authors.lastname: Adam
authors.forename: Katharina
authors.initials: K
authors.lastname: Theobald
authors.forename: Daniel
authors.initials: D
authors.lastname: Lavall
authors.forename: Markus
authors.initials: M
authors.lastname: Grube
authors.forename: Heyo K
authors.initials: HK
authors.lastname: Kroemer
authors.forename: Sabine
authors.initials: S
authors.lastname: Ameling
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 / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001281:Atrial Fibrillation / Q000378:metabolism*; D015153:Blotting, Western; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism*; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D006325:Heart Atria / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D008249:Protein-Lysine 6-Oxidase / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C526316:CCN2 protein, rat; D000804:Angiotensin II; D055513:Connective Tissue Growth Factor; D003094:Collagen; D008249:Protein-Lysine 6-Oxidase; C499134:Rac1 protein, rat; D020830:rac1 GTP-Binding Protein