title: Inhibition of aldosterone synthase (CYP11B2) by torasemide prevents atrial fibrosis and atrial fibrillation in mice.
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 (50μM, 24h) but not furosemide (50μM, 24h) 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 (8months) with torasemide (10mg/kg/day), furosemide (40mg/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.
authors.affiliation: Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, D-66421 Homburg/Saar, Germany. Electronic address: oliver.adam@uks.eu.
authors.forename: Oliver
authors.initials: O
authors.lastname: Adam
authors.affiliation: Helmholtz-Institute for Pharmaceutical Research Saarland, Pharmaceutical and Medicinal Chemistry, Saarland University, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Zimmer
authors.affiliation: Helmholtz-Institute for Pharmaceutical Research Saarland, Pharmaceutical and Medicinal Chemistry, Saarland University, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Hanke
authors.affiliation: Helmholtz-Institute for Pharmaceutical Research Saarland, Pharmaceutical and Medicinal Chemistry, Saarland University, Germany.
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
authors.affiliation: Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, D-66421 Homburg/Saar, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Klemmer
authors.affiliation: Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, D-66421 Homburg/Saar, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Böhm
authors.affiliation: Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, D-66421 Homburg/Saar, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Laufs
mesh_terms: D000450:Aldosterone / Q000378:metabolism; D000818:Animals; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000201:enzymology; D064752:Atrial Remodeling / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D024022:Fibrillar Collagens / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis; D020128:Inhibitory Concentration 50; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008249:Protein-Lysine 6-Oxidase / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology*; D000077786:Torsemide
chemical_list: C526318:CCN2 protein, mouse; D002316:Cardiotonic Agents; D024022:Fibrillar Collagens; C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D013449:Sulfonamides; D055513:Connective Tissue Growth Factor; D000450:Aldosterone; D019405:Cytochrome P-450 CYP11B2; D008249:Protein-Lysine 6-Oxidase; D000077786:Torsemide
keywords: Atrial fibrillation; Fibrosis; Loop diuretics; Torasemide