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.