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

Published on Oct 1, 2019in Biochemical Pharmacology4.825
· DOI :10.1016/j.bcp.2019.07.001
Daniel Lavall7
Estimated H-index: 7
,
Nadine Jacobs1
Estimated H-index: 1
(Saarland University)
+ 3 AuthorsUlrich Laufs67
Estimated H-index: 67
Sources
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 ± 25.6 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 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 ± 1.4 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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References42
Newest
#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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Abstract Managing the cardiovascular complications of renal failure is a major therapeutic challenge in clinical practice. Mineralocorticoid Receptor (MR) blockade is a highly effective strategy for the management of heart failure, but the use of MR antagonists (MRA) is limited by their side effects rendering them contraindicated in patients with renal failure. Finerenone is a new non-steroidal MRA that shows fewer hyperkaliaemic events than the traditional steroidal MRAs and could therefore rep...
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#1Jana GruneH-Index: 5
#2Niklas BeyhoffH-Index: 3
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Mineralocorticoid receptor antagonists (MRAs) reduce morbidity and mortality in chronic heart failure. Novel nonsteroidal MRAs are currently developed and need to be pharmacologically characterized...
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#1Davor Vukadinović (Saarland University)H-Index: 3
#2Daniel Lavall (Saarland University)H-Index: 7
Last. Michael Böhm (Saarland University)H-Index: 119
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Background Mineralocorticoid receptor antagonists (MRA) improve survival in heart failure with reduced ejection fraction but are often underused, mostly due to concerns of hyperkalemia. Because hyperkalemia occurs also on placebo, we aimed to determine the truly MRA-related rate of hyperkalemia. Methods We performed a meta-analysis including randomized, placebo-controlled trials reporting hyperkalemia on MRAs in patients after myocardial infarction or with chronic heart failure. We evaluated the...
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#1Peter Bramlage (University of Seville)H-Index: 36
#2Stephanie L. SwiftH-Index: 1
Last. Roland E. SchmiederH-Index: 87
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Pharmaceutical antagonism of the mineralocorticoid receptor (MR) can protect against organ damage caused by elevated aldosterone levels in patients experiencing heart failure (HF), chronic kidney disease (CKD), primary aldosteronism, and hypertension. While traditional steroid-based MR antagonists effectively reduce mortality rates and extend patient survival, their broad application has been limited by significant side effects, most notably hyperkalaemia. Recently, finerenone (BAY 94-8862) has ...
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#1Daniel Lavall (Saarland University)H-Index: 7
#2Pia Schuster (Saarland University)H-Index: 2
Last. Ulrich Laufs (Saarland University)H-Index: 67
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Abstract The aim of the study was to characterize the role of Rac1 GTPase for the mineralocorticoid receptor (MR)-mediated pro-fibrotic remodeling. Transgenic mice with cardiac overexpression of constitutively active Rac1 (RacET) develop an age-dependent phenotype with atrial dilatation, fibrosis, and atrial fibrillation. Expression of MR was similar in RacET and WT mice. The expression of 11β hydroxysteroid dehydrogenase type 2 (11β-HSD2) was age-dependently up-regulated in the atria and the le...
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#1Lionel LattenistH-Index: 2
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Acute kidney injury induced by ischemia/reperfusion (IR) is a frequent complication in hospitalized patients. Mineralocorticoid receptor antagonism has shown to be helpful against renal IR conseque...
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#1Lionel LattenistH-Index: 2
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Acute kidney injury induced by ischemia/reperfusion (IR) is a frequent complication in hospitalized patients. Mineralocorticoid receptor antagonism has shown to be helpful against renal IR consequences; however, the potential benefit of novel nonsteroidal mineralocorticoid receptor antagonists such as finerenone has to be further explored. In this study, we evaluated the efficacy of finerenone to prevent the acute and chronic consequences of ischemic acute kidney injury. For the acute study (24 ...
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#1Gerasimos Filippatos (UoA: National and Kapodistrian University of Athens)H-Index: 92
#2Stefan D. AnkerH-Index: 122
Last. Bertram Pitt (UM: University of Michigan)H-Index: 101
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Aims To evaluate oral doses of the non-steroidal mineralocorticoid receptor antagonist finerenone given for 90 days in patients with worsening heart failure and reduced ejection fraction and chronic kidney disease and/or diabetes mellitus. Methods and results Miner Alocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF) was a randomized, double-blind, phase 2b multicentre study (ClinicalTrials.gov: [NCT01807221][1]). Of 1286 screened patients, 1066 were randomized. Patients r...
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#1Jana GruneH-Index: 5
#2Verena BenzH-Index: 9
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Pharmacological blockade of mineralocorticoid receptors (MR) is known as an efficacious therapy in chronic heart failure. Therapy with steroidal MR antagonists such as spironolactone or eplerenone (EPL) is often limited because of side effects. Recently, a new highly selective and potent, nonsteroidal MR antagonist, finerenone (FIN), has been developed. To investigate the effects of FIN on pressure-induced cardiac hypertrophy, the transverse aortic constriction (TAC) model was used in C57BL/6 mi...
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Myocardial fibrosis is a significant global health problem associated with nearly all forms of heart disease. Cardiac fibroblasts comprise an essential cell type in the heart that is responsible for the homeostasis of the extracellular matrix; however, upon injury, these cells transform to a myofibroblast phenotype and contribute to cardiac fibrosis. This remodeling involves pathological changes that include chamber dilation, cardiomyocyte hypertrophy and apoptosis, and ultimately leads to the p...
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