The Mineralocorticoid Receptor in Heart

Abstract

See related article, pp 746–754 The mineralocorticoid receptor (MR) antagonists (MRAs) spironolactone and eplerenone have beneficial effects in patients with heart failure (HF) or left ventricular dysfunction.1 This underscores the major role of an inadequate hormonal stimulation leading to MR activation in HF. However, the actions of MRAs are complex and several questions remained unsolved. Which biochemical pathways are activated by the hormone that binds the cardiac MR? Which hormone binds the cardiac MR? In which pathological settings are the MRAs most appropriately used? The MR is the intracellular receptor of aldosterone. The hormone-receptor complex binds to a specific DNA sequence and triggers the transcription of target genes. In epithelial cells, the induced genes are mostly involved in the control of sodium reabsorption. However, the link between the beneficial effects of MRA in HF and these actions related to sodium control are unclear. Spironolactone is efficient in HF patients at a subhypotensive dose that likely did not involve diuretic effects. This suggests that spironolactone action in this setting was, at least in part, directed toward the MR of nonepithelial cells. Disappropriately increased levels of aldosterone in plasma are associated with inflammation and fibrosis in heart and blood vessels. Indeed, improved outcomes with spironolactone in HF have been linked to the antifibrotic effects of spironolactone. The MR is expressed in several cardiac cell types, cardiomyocytes and fibroblasts, and in vascular endothelial and smooth muscle cells, raising the question of its function in these tissues. Genetic technologies in mice have allowed selective deletion or overexpression of MR in different cardiac cell types. These tricky experimentations give novel and interesting informations. The study …