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The non-steroidal mineralocorticoid receptor antagonist finerenone prevents cardiac fibrotic remodeling

Published on Oct 1, 2019in Biochemical Pharmacology4.83
· DOI :10.1016/j.bcp.2019.07.001
Daniel Lavall6
Estimated H-index: 6
,
N. Jacobs (Saarland University)+ 3 AuthorsUlrich Laufs68
Estimated H-index: 68
Abstract
Abstract Mineralocorticoid receptor (MR) overactivation promotes cardiac fibrosis. We studied the ability of the non-steroidal MR antagonist finerenone to prevent fibrotic remodeling. In neonatal rat cardiac fibroblasts, finerenone prevented aldosterone-induced nuclear MR translocation. Treatment with finerenone decreased the expression of connective tissue growth factor (CTGF) (74±15% of control, p=0.005) and prevented aldosterone-induced upregulation of CTGF and lysyl oxidase (LOX) completely. Finerenone attenuated the upregulation of transforming growth factor s (TGF-s), which was induced by the Rac1 GTPase activator L-buthionine sulfoximine. Transgenic mice with cardiac-specific overexpression of Rac1 (RacET) showed increased left ventricular (LV) end-diastolic (63.7±8.0 vs. 93.8±25.6µl, p=0.027) and end-systolic (28.0±4.0 vs. 49.5±16.7µl, p=0.014) volumes compared to wild-type FVBN control mice. Treatment of RacET mice with 100ppm finerenone over 5 months prevented LV dilatation. Systolic and diastolic LV function did not differ between the three groups. RacET mice exhibited overactivation of MR and 11s hydroxysteroid dehydrogenase type 2. Both effects were reduced by finerenone (reduction about 36%, p=0.030, and 40%, p=0.032, respectively). RacET mice demonstrated overexpression of TGF-s, CTGF, LOX, osteopontin as well as collagen and myocardial fibrosis in the left ventricle. In contrast, expression of these parameters did not differ between finerenone-treated RacET and control mice. Finerenone prevented left atrial dilatation (6.4±1.5 vs. 4.7±1.4mg, p=0.004) and left atrial fibrosis (17.8±3.1 vs. 12.8±3.1%, p=0.046) compared to vehicle-treated RacET mice. In summary, finerenone prevented from MR-mediated structural remodeling in cardiac fibroblasts and in RacET mice. These data demonstrate anti-fibrotic myocardial effects of finerenone.
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#1Benjamin Bonnard (French Institute of Health and Medical Research)H-Index: 1
#2Marie Pieronne-Deperrois (French Institute of Health and Medical Research)H-Index: 1
Last.Smail Messaoudi (French Institute of Health and Medical Research)H-Index: 4
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#1Daniel Lavall (Saarland University)H-Index: 6
#2Pia Schuster (Saarland University)H-Index: 2
Last.Ulrich Laufs (Saarland University)H-Index: 68
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#1Joshua G. Travers (Cincinnati Children's Hospital Medical Center)H-Index: 6
#2Fadia A. Kamal (Cincinnati Children's Hospital Medical Center)H-Index: 3
Last.Burns C. Blaxall (Cincinnati Children's Hospital Medical Center)H-Index: 29
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