ALDOSTERONE AND MINERALOCORTICOID RECEPTORS IN REGULATION OF THE CARDIOVASCULAR SYSTEM AND PATHOLOGICAL REMODELLING OF THE HEART AND ARTERIES

摘要

In the review we discuss the role of mineralocorticoid receptors (MRs) in regulation and pathological remodelling of the cardiovascular system and the therapeutic potential of pharmacological targeting of MRs in cardiovascular diseases. MRs are expressed in organs involved in cardiovascular homeostasis: brain, heart, kidneys and vessels. The excessive activation of MRs has deleterious effects on the cardiovascular system through sympatho-excitation, elevated salt appetite, and renal retention of salt with consequent positive sodium balance, fibrosis and remodelling of the heart and arteries, and with propensity for atrial and ventricular arrhythmias. Hence, it provides basis for a common pathophysiological milieu of hypertension and heart failure. Furthermore, MR-mediated changes in the cardiovascular system are potentiated by renin-angiotensin system and activation of angiotensin type 1 receptors. Due to low selectivity, MRs bind both aldosterone and GCs – cortisol in humans and corticosterone in laboratory rodents. The binding of GCs to MRs is determined by availability of tissue specific 11β-hydroxysteroid dehydrogenase of type 1 (11β-HSD1) or type 2 (11β-HSD2). 11β-HSD1 metabolizes GCs to either active or inactive metabolites depending on the presence of special cofactors, whereas 11β-HSD2 transforms GCs only into inactive metabolites allowing for selective stimulation of MRs by aldosterone. 11β-HSD2 is expressed in the vascular wall, renal epithelium and some groups of cardiovascular neurons in the brain. In contrast, cardiac expression of 11β-HSD2 is low, thus, both aldosterone and GCs interact with cardiac MRs. The importance of MRs in the cardiovascular pathology is reflected in clinical guidelines that recommend use of MR blockers, spironolactone and eplerenone, in the treatment of heart failure, myocardial infarction and hypertension. Furthermore, new MR blockers and selective inhibitors of 11β-HSD1 have been developed and are currently tested in clinical trials.