Inhibition of aldosterone synthase (CYP11B2) by torasemide prevents atrial fibrosis and atrial fibrillation in mice. (August 2015)

• Record Type: Journal Article
• Authors: Adam, Oliver; Zimmer, Christina; Hanke, Nina; Hartmann, Rolf W.; Klemmer, Birgit; Böhm, Michael; Laufs, Ulrich
• Is Part Of: Journal of molecular and cellular cardiology. Volume 85(2015:Aug.)
• Page Start: 140
• Page End: 150
• Publication Date: 2015-08
• Subjects: AF atrial fibrillation -- AngII angiotensin II -- CTGF connective tissue growth factor -- CY11B2 aldosterone synthase -- LA left atrium -- LOX lysyloxidase -- miR-21 microRNA-21 -- MR mineralocorticoid receptors -- RacET transgenic mice with cardiac overexpression of Rac1 GTPase -- SR sinus rhythm -- WT wild-type mice; Atrial fibrillation -- Fibrosis -- Loop diuretics -- Torasemide; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2015.05.019
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Loop diuretics are used for fluid control in patients with heart failure. Furosemide and torasemide may exert differential effects on myocardial fibrosis. Here, we studied the effects of torasemide and furosemide on atrial fibrosis and remodeling during atrial fibrillation. In primary neonatal cardiac fibroblasts, torasemide (50 μM, 24 h) but not furosemide (50 μM, 24 h) reduced the expression of connective tissue growth factor (CTGF; 65 ± 6%) and the pro-fibrotic miR-21 (44 ± 23%), as well as the expression of lysyl oxidase (LOX; 57 ± 8%), a regulator of collagen crosslinking. Mineralocorticoid receptor (MR) expression and activity were not altered. Torasemide but not furosemide inhibited human aldosterone synthase (CYP11B2) activity in transfected lung fibroblasts (V79MZ cells) by 75 ± 1.8%. The selective CYP11B2 inhibitor SL242 mimicked the torasemide effects. Mice with cardiac overexpression of Rac1 GTPase (RacET), which develop atrial fibrosis and spontaneous AF with aging, were treated long-term (8 months) with torasemide (10 mg/kg/day), furosemide (40 mg/kg/day) or vehicle. Treatment with torasemide but not furosemide prevented atrial fibrosis in RacET as well as the up-regulation of CTGF, LOX, and miR-2, whereas MR expression and activity remained unaffected. These effects correlated with a reduced prevalence of atrial fibrillation (33% RacET + Tora vs. 80% RacET). Torasemide but not furosemide inhibits CYP11B2 activity and reduces the expression of CTGF, LOX, and miR-21. These effects are associated with prevention of atrial fibrosis and a reduced prevalence of atrial fibrillation in mice. Highlights: Torsemide inhibits aldosterone synthase activity. Torasemide reduces fibrosis in vitro and in vivo. Torasemide reduces atrial fibrillation in vivo. Aldosterone synthase inhibition reduces fibrosis in vitro.