A New Connection: Myeloid Mineralocorticoid Receptor and Cardiovascular Disease

Abstract

Mineralocorticoid Receptor (MR) is a classic steroid hormone receptor. Its traditional role is to mediate aldosterone to control electrolyte homeostasis and blood pressure via renin-angiotensin system. Besides aldosterone, MR can also bind to glucocorticoids. In aldosterone sensitive tissues such as kidney, 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) inactivates glucocorticoids and makes MR binding to aldosterone possible. In tissues lack 11βHSD2, MR is presumably occupied by glucocorticoids. The functions of MR in these tissues are largely unknown. Randomized Aldactone Evaluation Study (RALES) and Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) successfully demonstrated cardiovascular benefits of blocking MR with antagonists. However, the mechanisms have not been clearly delineated. Macrophage polarization, a phenotype that macrophages polarize to distinct functional states such as classically activation and alternatively activation, has emerged as an important control element in cardiovascular diseases (CVD). Recent studies have shown that MR controls macrophage polarization and that deletion of MR  in myeloid cells  protects cardiac and vascular damages under pathological stress. These studies present a great opportunity for developing new antagonists to target myeloid MR specifically in order to improve specificity and effectiveness of this class of drug in CVD.