Selective Mineralocorticoid Receptor Cofactor Modulation as Molecular Basis for Finerenone's Antifibrotic Activity
| Autor: | Michael Schupp, Annelie Blumrich, Robert Klopfleisch, Peter Kolkhof, Ulrich Kintscher, Anna Foryst-Ludwig, René Houtman, Sarah Brix, Iris R. Betz, Zsofia Ban, Elia Smeir, Remigiusz Chudek, Philipp Stawowy, Jana Grune, Niklas Beyhoff |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Finerenone Cardiac fibrosis Biological Availability 030204 cardiovascular system & hematology Pharmacology 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Mineralocorticoid receptor Fibrosis Internal Medicine medicine Animals Myocytes Cardiac Naphthyridines Mineralocorticoid Receptor Antagonists Heart Failure Cofactor binding Aldosterone Chemistry Tenascin medicine.disease Eplerenone Disease Models Animal 030104 developmental biology Gene Expression Regulation Heart failure cardiovascular system medicine.drug |
| Zdroj: | Hypertension (Dallas, Tex. : 1979). 71(4) |
| ISSN: | 1524-4563 |
| Popis: | Mineralocorticoid receptor antagonists (MRAs) reduce morbidity and mortality in chronic heart failure. Novel nonsteroidal MRAs are currently developed and need to be pharmacologically characterized in comparison to classical steroidal MRAs. A mouse model of cardiac fibrosis induced by short-term isoproterenol injection was used to compare the nonsteroidal MRA finerenone and the steroidal MRA eplerenone in equi-efficient systemic MR blocking dosages. Molecular mechanisms were studied in MR-expressing H9C2/MR+ cardiomyocytes and in MR transcriptional cofactor binding assays. Both MRAs significantly inhibited an isoproterenol-mediated increase of left ventricular mass. Isoproterenol-induced cardiac fibrosis and macrophage invasion were potently blocked by finerenone, whereas eplerenone had no significant effect. Speckle tracking echocardiography revealed a significant improvement of global longitudinal peak strain by finerenone, an effect less prominent with eplerenone. Antifibrotic actions of finerenone were accompanied by a significant inhibition of profibrotic cardiac TNX ( tenascin-X ) expression, a regulation absent with eplerenone. Finally, we show a higher potency/efficacy and inverse agonism of finerenone versus eplerenone in MR transcriptional cofactor binding assays indicating differential MR cofactor modulation by steroidal and nonsteroidal MRAs. This study demonstrates that the nonsteroidal MRA finerenone potently prevents cardiac fibrosis and improves strain parameters in mice. Cardiac antifibrotic actions of finerenone may result from the inhibition of profibrotic TNX gene expression mediated by differential MR cofactor binding. Selective MR cofactor modulation provides a molecular basis for distinct (pre)-clinical actions of nonsteroidal and steroidal MRAs. |
| Databáze: | OpenAIRE |
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