The mineralocorticoid receptor promotes pro-fibrotic remodeling in atrial fibrillation

Abstract

Listen

Translate article

Purpose: We studied the role of the mineralocorticoid receptor (MR) for the signalling that promotes atrial fibrosis. Methods and results: Left atrial myocardium (LA) of patients with atrial fibrillation (AF) had increased hydroxyproline content (425±103%) compared to patients matched for atrial size in sinus rhythm (SR). AF patients showed similar expression of MR but had increased expression of 11β hydroxysteroid dehydrogenase type 2 (11β-HSD2; 376±115%), a glucocorticoid inactivating enzyme providing minderalocorticoid access to MR. Hydroxyproline in LA correlated with upregulated 11β-HSD2, connective tissue growth factor (CTGF) and secreted protein acidic and rich in cysteine (SPARC). In cultured cardiac fibroblasts, aldosterone increased hydroxyproline expression (244±46%), which was completely prevented by BR-4628, a dihydropyridine-derived non-steroidal and selective MR antagonist, and by spironolactone. Aldosterone and TGF-β enhanced the expression of CTGF (207±34% and 176±22%, respectively), and BR-4628 as well as spironolactone prevented these effects. Compared to control, CTGF expression was diminished with either BR-4628 or spironolactone treatment (59±17% and 51±155%, respectively). The Rho kinase inhibitor Y-27632 decreased both aldosterone and TGF-β induced CTGF upregulation (52±15% and 95±8%, respectively), whereas the RhoA activator CN03 increased CTGF expression (206±28%). This effect persisted after BR-4628 or spironolactone pre-treatment. CTGF and aldosterone increased lysyl oxidase (LOX) expression (194±19% and 272±37%, respectively). The aldosterone but not the CTGF effect was reduced by MR antagonists indicating that CTGF induces LOX expression downstream of the MR. Aldosterone elevated miR-21 expression (415±120%) and suppressed the miR-21 target Sprouty-1 (43±8%), both effects were prevented by BR-4628 and spironolactone. All reported effects are significant with p<0.05. Conclusions: Mineralocorticoid receptor signalling through hydroxyproline, CTGF, LOX and miR-21 contributes to pro-fibrotic remodeling. Inhibition of the MR pathways may therefore represent a target for the prevention of fibrosis which is a substrate for atrial fibrillation.