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.
Highlights
Mineralocorticoid Receptor Gene and Protein StructureThe mineralocorticoid receptor (MR) is a ligand-dependent transcription factor with aldosterone as an endogenous ligand in humans
Treatment with valproic acid (VPA) enhanced MR acetylation and increased histone-3-acetylation (H3Ac) and trimethylation (H3K4me3) in the promoter regions of MR target genes, expression of MR target genes was decreased, and the development of hypertension in deoxycorticosterone acetateinduced hypertensive rats and spontaneously hypertensive rats (SHR) was prevented (Seok et al, 2016). These results suggest that histone deacetylases (HDAC) inhibition attenuates the development of hypertension in SHR through acetylation of MR and independent of histone effects
Besides exerting classical epithelial effects on volume-and electrolyte homeostasis, the MR has a large impact on cardiovascular pathophysiology with cell-type-specific and context-dependent functions
Summary
Mineralocorticoid Receptor Gene and Protein StructureThe MR is a ligand-dependent transcription factor with aldosterone as an endogenous ligand in humans. Besides a ligand-binding pocket, the LBD possesses several chaperone interaction points, a nuclear localization signal, an area involved in heterodimerization with the GR, and the transcriptional activation functional domain 2 (AF-2) (Savory et al, 2001; Bain et al, 2007). This suggests that CDK5 through phosphorylation mediates the interaction of the MR with co-regulators and thereby modulates its transcriptional activity without affecting hormone binding or receptor translocation, similar as has been demonstrated for the GR (Kino et al, 2007).
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