Aldosterone/Mineralocorticoid Receptor Downstream Targets as Novel Therapeutic Targets to Prevent Cardiovascular Remodeling

Abstract

The incidence of heart failure (HF) is increasing because of aging of the population. Despite optimal therapy, patients with HF experience disease progression associated with high mortality rates. HF is still the first cause of hospital admission in subjects aged >65 years. The obvious solution for HF epidemics is to prevent new-onset HF with therapies directed specifically to mechanistic targets that are involved in the transition to HF. The mineralocorticoid receptor (MR) and its natural ligand, the hormone aldosterone (Aldo), play important roles during cardiac and arterial remodeling, but the underlying effects are still not understood. MR antagonists are highly recommended for treatment of systolic symptomatic HF. However, adverse effects limit their use in clinical practice. Galectin-3 (Gal-3), neutrophil gelatinase-associated lipocalin (NGAL), and cardiotrophin-1 (CT-1) have been identified as highly focused targets controlling downstream key MR-mediated HF mechanisms. Therefore, interfering with mechanistic pathways involved in downstream MR activation may provide therapeutic alternatives to MR antagonists. The aim of this review is to focus on the role of the MR biotargets in cardiovascular remodeling.

Sex-Related Signaling of Aldosterone/Mineralocorticoid Receptor Pathway in Calcific Aortic Stenosis

“…activation of the Aldo/MR pathway is involved in renal and cardiovascular remodeling. 8,9 Importantly, Aldo contributes to vascular calcification by directly stimulating osteogenic differentiation and calcification of vascular cells in a MR-dependent manner. [10][11][12] Interestingly, MR and 11βHSD2 are expressed in cardiac valves and in valve interstitial cells (VICs).…”

Sex-Related Signalling of Aldosterone/Mineralocorticoid Receptor Pathway in Calcific Aortic Stenosis

“…The corticosteroid hormone aldosterone (Aldo) is the agonist of the mineralocorticoid receptor (MR). The activation of the Aldo/MR pathway is involved in renal and cardiovascular remodeling (Ibarrola et al, 2019;Tesch & Young, 2017). Importantly, Aldo contributes to vascular calcification by directly stimulating osteogenic differentiation and calcification of vascular cells in a MR-dependent manner (Jaffe et al, 2007;Jaffe & Mendelsohn, 2005;Voelkl et al, 2013).…”

Mineralocorticoid receptor in cardiovascular diseases—Clinical trials and mechanistic insights

“…Aldosterone, a mineralocorticoid hormone produced by the adrenal gland (Bollag, 2014), is the agonist of the mineralocorticoid receptor (NR3C2). Aldosterone/mineralocorticoid receptor pathway is a potent mediator of cardiac remodelling and LV dysfunction (Ibarrola et al, 2019). Mineralocorticoid receptor antagonists mainly comprise the steroidal spironolactone and eplerenone, and the nonsteroidal finerenone.…”