期刊
BIOCHEMICAL PHARMACOLOGY
卷 168, 期 -, 页码 173-183出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2019.07.001
关键词
Connective tissue growth factor (CTGF); Fibrosis; Mineralocorticoid receptor; Transforming growth factor beta (TGF-beta); Collagen
资金
- Bayer AG
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 beta (TGF-beta), 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 mu l, p = 0.027) and end-systolic (28.0 +/- 4.0 vs. 49.5 +/- 16.7 mu l, 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 11 beta 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-beta, 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.
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