Posttranslational Modifications of the Mineralocorticoid Receptor and Cardiovascular Aging

Abstract

During aging, the cardiovascular system is especially prone to a decline in function and to life-expectancy limiting diseases. Cardiovascular aging is associated with increased arterial stiffness and vasoconstriction as well as left ventricular hypertrophy and reduced diastolic function. Pathological changes include endothelial dysfunction, atherosclerosis, fibrosis, hypertrophy, inflammation, and changes in micromilieu with increased production of reactive oxygen and nitrogen species. The renin-angiotensin-aldosterone-system is an important mediator of electrolyte and blood pressure homeostasis and a key contributor to pathological remodeling processes of the cardiovascular system. Its effects are partially conveyed by the mineralocorticoid receptor (MR), a ligand-dependent transcription factor, whose activity increases during aging and cardiovascular diseases without correlating changes of its ligand aldosterone. There is growing evidence that the MR can be enzymatically and non-enzymatically modified and that these modifications contribute to ligand-independent modulation of MR activity. Modifications reported so far include phosphorylation, acetylation, ubiquitination, sumoylation and changes induced by nitrosative and oxidative stress. This review focuses on the different posttranslational modifications of the MR, their impact on MR function and degradation and the possible implications for cardiovascular aging and diseases.

Keywords: acetylation; cardiovascular aging; mineralocorticoid receptor; oxidation; phosphorylation; posttranslational modification; sumoylation; ubiquitination.

FIGURE 1

hMR comprises 984 amino acids with an N-terminal domain (NTD), a DNA-binding domain (DBD), a hinge region and a ligand binding domain (LBD). Located within the NTD is an activation function 1 (AF-1) that is divided by an inhibitory domain (ID) into two parts, AF-1a and AF-1b. AF-2 is located in the LBD. Several nuclear localization signals (NLS) and putative nuclear export signals (NES) have been described.

FIGURE 2

In its unliganded state the MR is monoubiquitinated and located in the cytosol with chaperone molecules like HSP90. Its endogenous ligand aldosterone binds to MR in the cytosol and thereby triggers nuclear translocation. Ligand binding is inhibited by MR oxidation. In intercalated cells, autophagy activating kinase 1 (Ulk1) phosphorylates MR S843 in the LBD, mitigates its affinity for agonists and reducing its transcriptional activity. Peroxynitrite (ONOO-) can cause ligand-independent nuclear translocation and activation of MR. Inhibition of HSP90 or activation by aldosterone causes polyubiquitination of MR and degradation. ERK1/2 and PKC also modulate MR polyubiquitination and degradation. Positive regulators of MR transactivation activity are PKCa and CK2. In the prescence of cytokines, CK2 inhibits GRE signaling but promotes NFKB signaling and transcription of pro-inflammatory cytokines. CDK5 inhibits MR transactivation in neuronal cells. Acetylation (Ac) and SUMOylation (Su) lead to modulation of aldosterone-activated MR transactivation by direct and indirect effects. NO attenuates binding of MR to DNA, consequently reducing the MR’s transcriptional activity (↑ = stimulatory effect; ↓ = inhibitory effect).

FIGURE 3

Mineralocorticoid receptor undergoes enzymatic and non-enzymatic posttranslational modifications, affecting the basal condition of the receptor, ligand binding, shuttling to the nucleus, DNA interaction and transactivation activity. Among enzymatic modifications phosphorylation (P), acetylation (Ac), ubiquitination (Ub), SUMOylation (Su) has been well-described. Increased ROS and RNS production during aging causes non-enzymatic alterations. Possible consequences are summarized in this figure.