P5442The non-steroidal mineralocorticoid receptor antagonist finerenone prevents structural cardiac remodeling

CTGF公司 医学 盐皮质激素受体 内科学 赖氨酰氧化酶 心脏纤维化 内分泌学 纤维化 螺内酯 下调和上调 醛固酮 受体 生长因子 细胞外基质 生物 细胞生物学 基因 生物化学
作者
Daniel Lavall,Nadine Jacobs,Felix Mahfoud,Peter Kolkhof,Michael Böehm,Ulrich Laufs
出处
期刊:European Heart Journal [Oxford University Press]
卷期号:40 (Supplement_1)
标识
DOI:10.1093/eurheartj/ehz746.0398
摘要

Abstract Background Mineralocorticoid receptor (MR) signaling mediates cardiac fibrosis. We studied the ability of the non-steroidal MR antagonist finerenone to prevent fibrotic remodeling. Methods and results 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. Transforming growth factor β (TGF-β) upregulation induced through the Rac1 GTPase activator L-buthionine sulfoximine was attenuated by finerenone. 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 was similarly preserved in the three groups. RacET mice exhibited overactivation of MR and 11β 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-β, CTGF, LOX 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. The prevalence of atrial arrhythmias at 5 months did not differ between finerenone- and vehicle-treated RacET mice. Conclusion Finerenone prevented from MR-mediated structural remodeling in cardiac fibroblasts and in RacET mice. These data demonstrate anti-fibrotic myocardial properties of finerenone.
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