The main target for inhibiting mineralocorticoid receptor-mediated signaling in cardiovascular diseases

The renin–angiotensin–aldosterone system has a crucial role in the development and progression of cardiovascular diseases.1–3 Angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists are widely used in patients with cardiovascular diseases or those with risk factors (for example, hypertension and diabetes mellitus). Aldosterone is a downstream effector in this system, but its level increases in 30–40% of patients with upstream blockade of this system with an angiotensin-converting enzyme inhibitor and/or angiotensin receptor antagonist over the long term (that is, aldosterone breakthrough). Following binding to the mineralocorticoid receptor (MR), aldosterone induces detrimental cardiovascular remodeling through processes such as myocyte and smooth muscle cell hypertrophy and collagen accumulation. Previous clinical studies have reported that MR blockade improved the mortality and morbidity of patients with heart failure or myocardial infarction, even if an angiotensin-converting enzyme inhibitor and/or angiotensin receptor antagonist was prescribed.4–6 Despite such clinical evidence, MR blockers are underused in clinical practice,7 because abrupt increases in the rate of prescriptions for MR blockers after the publication of clinical trials were followed by increased hyperkalemia-associated morbidity and mortality.8 Therefore, identifying a master regulator of the MRmediated pathway could provide more beneficial and/or less adverse effects in treating cardiovascular diseases. Although MR blockade has been called ‘aldosterone blockade’, this term may be incorrect in reference to several organs. Both glucocorticoids and mineralocorticoids have an affinity for the MR.9 The glucocorticoid cortisol/corticosterone is converted by 11b-hydroxysteroid dehydrogenase type 2 (11b-HSD2) to an inactive metabolite that cannot bind to MR, which results in the selective binding of aldosterone to the MR. However, 11b-HSD2 is absent in several organs, such as the heart and hypothalamus, and cortisol/corticosterone is present at a 100–1000-fold greater concentration than aldosterone.3,10 Thus, glucocorticoids have been speculated to exert their effects through the MR in the heart; however, the details of this mechanism remain unclear. Although glucocorticoids induce myocyte hypertrophy, the effects of glucocorticoids can be inhibited by a glucocorticoid receptor blocker, but not by an MR blocker, in cultured myocytes.11 The extent of the contribution of cortisol/corticosterone to MR activation remains unclear, but inhibition of this pathway may be effective in inactivating MR-mediated signaling under certain conditions. Alternatively, previous studies have suggested non-genomic actions of aldosterone independent of MR-mediated signaling.12 The aldosterone receptors involved in the non-genomic actions have not been identified, which indicates that aldosterone blockade is not equal to MR blockade. There are several mechanisms to activate MR-mediated signaling without increasing the ligands. First, MR is upregulated in pathological conditions,3,13 although the mechanisms for upregulation need to be clarified. Second, MR is degraded by proteasomes, and deubiquitylation may lead to MR stabilization. Third, desumoylation and cyclin-dependent kinase 5 induce the phosphorylation of multiple serines and threonines on the MR to enhance its transactivation.14,15 Fourth, Rac1 facilitates the nuclear translocation of the MR.16 Blockade of any of these phenomena may lead to the attenuation of MR-mediated signaling independent of antagonizing ligand binding to the MR. Recently, He et al.17 showed that MRinduced oxidative activation of Ca2þ /calmodulin-dependent protein kinase II (CaMKII) has a crucial role in MR-mediated signaling in myocytes (Figure 1). These authors showed that aldosterone activates NADPH oxidase through MR and that this process requires Rac1. Rac1-dependent activation of NADPH oxidase promotes the production of reactive oxygen species and subsequent oxidization of CaMKII in myocytes. This enhanced oxidization of CaMKII facilitates the expression of matrix metalloproteinase-9 (MMP9) through myocyte enhancer factor 2 (MEF2)-dependent transcription, leading to cardiac rupture following myocardial infarction. MR activation is well known to have a crucial role in the development of heart failure induced by pressure overload, and Backs et al.18 showed that knocking out the d isoform of CaMKII diminished pathological cardiac hypertrophy and remodeling in mice with pressure overload. Therefore, CaMKII may also contribute to the MRmediated effects in cardiovascular diseases other than myocardial infarction. In developed countries, the number of patients with heart failure is increasing, and their prognosis remains poor even after the increased prescription rate of angiotensinconverting enzyme inhibitors, angiotensin receptor antagonists, MR blockers and b-blockers. Myocardial infarction is a leading cause of heart failure. Several clinical studies Professor K. Yamamoto is at Division of Cardiovascular Medicine, Endocrinology and Metabolism, Department of Molecular Medicine and Therapeutics, Faculty of Medicine, Tottori University, Yonago, Japan E-mail: ykazuhiro@med.tottori-u.ac.jp Hypertension Research (2013) 36, 580–582 & 2013 The Japanese Society of Hypertension All rights reserved 0916-9636/13