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- Title
Role of miR-21 in the pathogenesis of atrial fibrosis.
- Authors
Adam, Oliver; Löhfelm, Björn; Thum, Thomas; Gupta, Shashi; Puhl, Sarah-Lena; Schäfers, Hans-Joachim; Böhm, Michael; Laufs, Ulrich
- 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.
- Subjects
HEART fibrosis; MICRORNA; CELLULAR signal transduction; GROWTH factors; ANGIOTENSIN II; LYSYL oxidase; MYOCARDIAL infarction
- Publication
Basic Research in Cardiology, 2012, Vol 107, Issue 5, p1
- ISSN
0300-8428
- Publication type
Article
- DOI
10.1007/s00395-012-0278-0