The mineralocorticoid receptor promotes fibrotic remodeling in atrial fibrillation.
We studied the role of the mineralocorticoid receptor (MR) in the signaling that promotes atrial fibrosis. Left atrial myocardium of patients with atrial fibrillation (AF) exhibited 4-fold increased hydroxyproline content compared with patients in sinus rhythm. Expression of MR was similar, as was 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which also increased. 11β-HSD2 converts cortisol to receptor-inactive metabolites allowing aldosterone occupancy of MR. 11β-HSD2 was up-regulated by arrhythmic pacing in cultured cardiomyocytes and in a mouse model of spontaneous AF (RacET). In cardiomyocytes, aldosterone induced connective tissue growth factor (CTGF) in the absence but not in the presence of cortisol. Hydroxyproline expression was increased in cardiac fibroblasts exposed to conditioned medium from aldosterone-treated cardiomyocytes but not from cardiomyocytes treated with both cortisol and aldosterone. Aldosterone increased connective tissue growth factor and hydroxyproline expression in cardiac fibroblasts, which were prevented by BR-4628, a dihydropyridine-derived selective MR antagonist, and by spironolactone. Aldosterone activated RhoA GTPase. Rho kinase inhibition by Y-27632 prevented CTGF and hydroxyproline, whereas the RhoA activator CN03 increased CTGF expression. Aldosterone and CTGF increased lysyl oxidase, and aldosterone enhanced miR-21 expression. MR antagonists reduced the aldosterone but not the CTGF effect. In conclusion, MR signaling promoted fibrotic remodeling. Increased expression of 11β-HSD2 during AF leads to up-regulation of collagen and pro-fibrotic mediators by aldosterone, specifically RhoA activity as well as CTGF, lysyl oxidase, and microRNA-21 expression. The MR antagonists BR-4628 and spironolactone prevent these alterations. MR inhibition may, therefore, represent a potential pharmacologic target for the prevention of fibrotic remodeling of the atrial myocardium.
Klinik für Innere Medizin III-Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes Kirrberger Strasse, 66421 Homburg/Saar, Germany. Electronic address: daniel.lavall@uks.eu.
Daniel
D
Lavall
Klinik für Innere Medizin III-Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes Kirrberger Strasse, 66421 Homburg/Saar, Germany.
Christian
C
Selzer
Klinik für Innere Medizin III-Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes Kirrberger Strasse, 66421 Homburg/Saar, Germany.
Pia
P
Schuster
Klinik für Innere Medizin III-Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes Kirrberger Strasse, 66421 Homburg/Saar, Germany.
Matthias
M
Lenski
Klinik für Innere Medizin III-Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes Kirrberger Strasse, 66421 Homburg/Saar, Germany.
Oliver
O
Adam
Klinik für Thorax- und Herz-Gefässchirurgie, Universitätsklinikum des Saarlandes, Kirrberger Strasse, 66421 Homburg/Saar, Germany.
Hans-Joachim
HJ
Schäfers
Klinik für Innere Medizin III-Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes Kirrberger Strasse, 66421 Homburg/Saar, Germany.
Michael
M
Böhm
Klinik für Innere Medizin III-Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes Kirrberger Strasse, 66421 Homburg/Saar, Germany.
Ulrich
U
Laufs
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000096:biosynthesis; D000818:Animals; D001281:Atrial Fibrillation / Q000473:pathology*; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D006325:Heart Atria / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism; D008875:Middle Aged; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D051381:Rats; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000502:physiology*; D013148:Spironolactone / Q000494:pharmacology; D015854:Up-Regulation
C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D055513:Connective Tissue Growth Factor; D013148:Spironolactone; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1
CTGF; Fibrosis; Heart; Lysyl Oxidase; MicroRNA; Mineralocorticoid Receptor