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

Biochem Pharmacol. 2019 Oct:168:173-183. doi: 10.1016/j.bcp.2019.07.001. Epub 2019 Jul 5.

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 ß (TGF-ß), 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 ± 25.6 µl, p = 0.027) and end-systolic (28.0 ± 4.0 vs. 49.5 ± 16.7 µl, p = 0.014) volumes compared to wild-type FVBN control mice. Treatment of RacET mice with 100 ppm 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 11ß 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-ß, 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 ± 1.4 mg, 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.

Keywords: Collagen; Connective tissue growth factor (CTGF); Fibrosis; Mineralocorticoid receptor; Transforming growth factor beta (TGF-β).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Atrial Remodeling / drug effects*
  • Cells, Cultured
  • Disease Models, Animal
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibrosis
  • Mice
  • Mice, Transgenic
  • Mineralocorticoid Receptor Antagonists / pharmacology*
  • Myocardium / cytology
  • Myocardium / pathology
  • Naphthyridines / pharmacology*
  • Neuropeptides / genetics
  • Neuropeptides / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Mineralocorticoid / metabolism*
  • Ventricular Remodeling / drug effects*
  • rac1 GTP-Binding Protein / genetics
  • rac1 GTP-Binding Protein / metabolism

Substances

  • Mineralocorticoid Receptor Antagonists
  • Naphthyridines
  • Neuropeptides
  • Rac1 protein, mouse
  • Receptors, Mineralocorticoid
  • finerenone
  • rac1 GTP-Binding Protein