Abstract 11898: Lysyl-Oxidase Mediated Regulation of Mir-21 and Spry1 Contributes to Strcutural Remodeling During Atrial Fibrillation
Introduction. Despite the importance of interstitial fibrosis for the pathogenesis of atrial remodeling and atrial fibrillation (AF)is the underlying signal transduction unclear. The microRNA-21 (miR-21) and its down-stream-target Sprouty 1 (Spry1) have been reported to regulate of fibrosis in the left ventricle. The role of miR-21 during atrial fibrillation is unknown.
Methods and Results: Therefore we investigated samples of the left atrial appendage (LA) from patients with AF showing higher collagen content compared to samples from sinus rhythm (SR) patients (n= 8 per group). LA of AF patients showed a 2.5-fold increased expression of miR-21 (280±81%) compared to SR. This was associated with a reduced protein expression of Spry1 (56±9%) as well as increased expression of the connective tissue growth factor (CTGF, 205±68%), lysyl-oxidase (LOX, 255±65%) and Rac-1 activity in the human atria. In order to test the underlying mechanism, neonatal cardiac fibroblasts were treated with the pro-fibrotic agents angiotensin II or CTGF which lead to increased miR-21expression and decreased Spry1 expression. Pre-treatment with the specific small molecule inhibitor of Rac1, NSC23766, reduced the AngII induced upregulation of miR-21 (385±75%) to 171±33%. Pre-incubation with a specific small molecule inhibitor of LOX (BAPN) potently prevented the angiotensin II as well as CTGF (435±77%) induced miR-21 expression. To further characterize the importance of Rac1 for this signalling in vivo, transgenic mice with cardiac overexpression (αMHC promoter) of Rac1 (RacET), which develop spontaneously AF at higher age, were compared to wildtype (WT). Atria of RacET mice showed upregulation of miR-21 expression (215±48%) and a reduced Spry1 protein expression (49±%) associated with an increased protein expression of LOX (187±7%). Treatment of RacET with rosuvastatin (0.4 mg/day po, 10 months) prevented these effects. All effects are significant with p<0.001-0.05.
Conclusion: Left atria of patients with AF are characterized by up-regulation of miR-21 und reduced expression of Spry1. Activation of Rac1 by angiotensin II leads to a LOX-mediated increase of miR-21 and down-regulation of Spry1 contributing to structural remodeling during atrial fibrillation.
- © 2011 by American Heart Association, Inc.