Hypertension | 2019
Mineralocorticoid Receptor Activation and Atrial Fibrosis.
Abstract
Aldosterone and mineralocorticoid receptor (MR) activation promote atrial fibrosis and fibrillation in rodent models. In this issue of Hypertension, Yi et al provide evidence that activation of osteoblast MR contributes to atrial fibrosis and fibrillation by increasing osteocalcin. Specifically, the authors studied transgenic mice that express human TGF (transforming growth factor)-β1 cDNA with a cysteine-to-serine substitution at amino acid 33, under the transcriptional regulation of the α-cardiac heavy chain promoter (TGF). These mice demonstrate atrial fibrosis but not ventricular fibrosis because of atrial-specific increases in TGF-β1 signaling. The authors crossed the mice with those with an osteoblastspecific knockout under the control of a tamoxifen-inducible Cre recombinase (MR). They found that TGF/MR mice were protected against atrial fibrosis and the development of atrial fibrillation compared with TGF/MR mice. The mice also had reduced circulating concentrations of osteocalcin and undercarboxylated osteocalcin. In a reconstitution experiment, the investigators found that treatment of the TGF/ MR mice with recombinant undercarboxylated osteocalcin for 4 weeks restored fibrosis. In cultured atrial fibroblasts, osteocalcin increased proliferation and migration through a GPRC6A (G protein-coupled receptor, family C, group 6, member A)-dependent mechanism involving upregulation of PKA (protein kinase A) and through an atrial MR-independent mechanism (Figure). This study extends a growing body of work describing the hormonal effects of osteoblast-derived osteocalcin, ably reviewed elsewhere. Osteocalcin in its circulating, undercarboxylated form promotes insulin secretion, enhances insulin sensitivity, and protects against diet-induced obesity. It seems paradoxical then that osteocalcin would promote atrial fibrosis and atrial fibrillation, a disease associated with obesity. Indeed, the intriguing study of Yi et al raises many new questions. For example, what is the endogenous ligand for the osteoblast MR? The affinity of the MR for cortisol (corticosterone in rodents) and aldosterone are similar. Because plasma cortisol concentrations exceed aldosterone concentrations by 100to 1000-fold, in most tissues the MR is activated by cortisol. In aldosterone-sensitive tissues, conversion of cortisol to the MR-inactive cortisone by 11βHSD2 (11β-hydroxysteroid dehydrogenase) confers specificity. 11β-HSD2 is expressed in rat and human osteosarcoma cell lines, whereas normal human adult osteoblasts express minimal 11β-HSD2. Yi et al demonstrated that corticosterone prevented aldosterone-induced expression of osteocalcin in the MC3T3-E1 osteoblast cell line, but this does not resolve the question of the endogenous ligand. Studies using transgenic overexpression of 11β-HSD2 in osteoblasts of TGF mice would shed light on the importance of endogenous glucocorticoids as osteoblast MR ligand. Osteoblast specific-deletion of the MR protected the mutant TGF-β transgenic mouse not only from fibrosis but also from susceptibility to high frequency stimulation-induced atrial fibrillation. The clinical significance of this relates to the observation that MR antagonism reduces atrial fibrillation in heart failure patients. Excess aldosterone in patients with an aldosterone-producing adenoma or adrenal hyperplasia is also associated with increased risk of atrial fibrillation compared with in patients with essential hypertension. Interestingly, treatment with an MR antagonist does not abolish the increased risk of atrial fibrillation but adrenalectomy does. Although it is tempting to speculate that aldosterone could promote atrial fibrillation through an MR-independent mechanism, it is more likely that some patients treated with an MR antagonist are not given doses sufficient to block the receptor. Hundemer et al reported that the effect of MR antagonist treatment on the incidence of atrial fibrillation in patients with primary hyperaldosteronism depends on whether renin increases or remains suppressed, an indicator of whether the MR is sufficiently blocked. Patients treated with an MR antagonist whose renin remained suppressed had an elevated risk of atrial fibrillation (adjusted hazard ratio, 2.55 [95% CI, 1.75–3.71]) compared with patients with essential hypertension, whereas those who underwent adrenalectomy or who were treated with an MR antagonist at a sufficient dose to increase renin did not. Does the study by Yi et al suggest that the beneficial effect of MR antagonism in preventing atrial fibrillation is mediated entirely by effects at the osteoblast MR to decrease osteocalcin? This is not likely. In fact, the same research group previously reported that eplerenone treatment decreases atrial fibrosis as well as fibronectin and CTGF (connective tissue growth factor) expression in the TGF mouse model. Further, in studies in atrial tissue and in cultured atrial fibroblasts The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Department of Medicine, Vanderbilt University Medical Center, Nashville, TN. Correspondence to Nancy J. Brown, Department of Medicine, Vanderbilt University Medical Center, D-3100 Medical Center N, Nashville, TN 37232. Email [email protected] Mineralocorticoid Receptor Activation and Atrial Fibrosis B-B-B-B-Bad to the Bone