title: Role of miR-21 in the pathogenesis of atrial fibrosis.
abstract: Atrial fibrosis is important for the pathogenesis of atrial fibrillation (AF) but the underlying signal transduction is incompletely understood. We therefore studied the role of microRNA-21 (miR-21) and its downstream target Sprouty 1 (Spry1) during atrial fibrillation. Left atria (LA) from patients with AF showed a 2.5-fold increased expression of miR-21 compared to matched LA of patients in sinus rhythm. Increased miR-21 expression correlated positively with atrial collagen content and was associated with a reduced protein expression of Spry1 and increased expression of connective tissue growth factor (CTGF), lysyl oxidase and Rac1-GTPase. Neonatal cardiac fibroblasts treated with angiotensin II (AngII) or CTGF showed an increased miR-21 and decreased Spry1 expression. Pretreatment with an inhibitor of Rac1 GTPase, NSC23766, reduced the AngII-induced upregulation of miR-21. A small molecule inhibitor of lysyl oxidase, BAPN, prevented the AngII as well as the CTGF-induced miR-21 expression. Transgenic mice with cardiac overexpression of Rac1, which develop spontaneous AF and atrial fibrosis with increasing age, showed upregulation of miR-21 expression associated with reduced Spry1 expression. miR-21 expression and signalling in vivo were prevented by long-term treatment of the mice with statins. Direct inhibition of miR-21 by antagomir-21 prevented fibrosis of the atrial myocardium post-myocardial infarction. Left atria of patients with atrial fibrillation are characterized by upregulation of miR-21 und reduced expression of Spry1. Activation of Rac1 by angiotensin II leads to a CTGF- and lysyl oxidase-mediated increase of miR-21 expression contributing to structural remodelling of the atrial myocardium.
authors: Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany. oliver.adam@uks.eu
authors: Oliver
authors: O
authors: Adam
authors: Björn
authors: B
authors: Löhfelm
authors: Thomas
authors: T
authors: Thum
authors: Shashi K
authors: SK
authors: Gupta
authors: Sarah-Lena
authors: SL
authors: Puhl
authors: Hans-Joachim
authors: HJ
authors: Schäfers
authors: Michael
authors: M
authors: Böhm
authors: Ulrich
authors: U
authors: Laufs
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D055513:Connective Tissue Growth Factor / Q000502:physiology; D055233:Cornified Envelope Proline-Rich Proteins / Q000032:analysis; D053487:DEAD-box RNA Helicases / Q000502:physiology; D005355:Fibrosis; D006325:Heart Atria / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000032:analysis / Q000502:physiology*; D008249:Protein-Lysine 6-Oxidase / Q000502:physiology; D043244:Ribonuclease III / Q000502:physiology; D020830:rac1 GTP-Binding Protein / Q000502:physiology
chemical_list: C526317:CCN2 protein, human; D055233:Cornified Envelope Proline-Rich Proteins; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; C524531:SPRR1A protein, human; D000804:Angiotensin II; D055513:Connective Tissue Growth Factor; D008249:Protein-Lysine 6-Oxidase; C408087:DICER1 protein, human; C517918:DROSHA protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases; D020830:rac1 GTP-Binding Protein