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Role of miR-21 in the pathogenesis of atrial fibrosis

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An Invited Editorial to this article was published on 17 July 2012

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.

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Acknowledgments

We thank Simone Jäger and Ellen Becker for their excellent technical assistance. Sources of funding: this study was supported by the Deutsche Forschungsgemeinschaft (KFO 196), the Universität des Saarlandes, the European Stroke Network (ESN) and the Ministerium für Wirtschaft und Wissenschaft des Saarlandes.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, 66424, Homburg/Saar, Germany

    Oliver Adam, Björn Löhfelm, Sarah-Lena Puhl, Michael Böhm & Ulrich Laufs

  2. Institut für Molekulare und Translationale Therapiestrategien (IMTTS), Medizinische Hochschule Hannover, Hannover, Germany

    Thomas Thum & Shashi K. Gupta

  3. Klinik für Thorax- und Herz-Gefäßchirurgie, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany

    Hans-Joachim Schäfers

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395_2012_278_MOESM1_ESM.doc

Supplement Fig. 1 Correlation between miR-21 expression (2−ΔΔct) in left atrial myocardium of patients with atrial fibrillation (AF); n = 8 per; r = 0.9728, p < 0.0001 (DOC 256 kb)

395_2012_278_MOESM2_ESM.doc

Supplement Fig. 2 Quantification of myocyte size in the atria of mice after myocardial infarction induced by LAD occlusion with (MI + Antag-21) and without antagomir-21 treatment (MI) compared to Sham; n = 4-5 per group, *p < 0.05 vs. Sham, #p < 0.05 vs MI. (DOC 117 kb)

395_2012_278_MOESM3_ESM.doc

Supplement Table 1 Patient characteristics ACE-I = angiotensin-converting enzyme inhibitor; AT antagonist = angiotensin receptor I antagonist; FS = fractional shortening; IVSd = interventricular septum; LA = left atrium; LVEDd = left ventricular end-diastolic diameter; LVEF = left ventricular ejection fraction; LVESd = left ventricular end-systolic diameter. (DOC 77 kb)

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Adam, O., Löhfelm, B., Thum, T. et al. Role of miR-21 in the pathogenesis of atrial fibrosis. Basic Res Cardiol 107, 278 (2012). https://doi.org/10.1007/s00395-012-0278-0

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