Novel Insights into the Crosstalk between Mineralocorticoid Receptor and G Protein-Coupled Receptors in Heart Adverse Remodeling and Disease
- PMID: 30486399
- PMCID: PMC6320977
- DOI: 10.3390/ijms19123764
Novel Insights into the Crosstalk between Mineralocorticoid Receptor and G Protein-Coupled Receptors in Heart Adverse Remodeling and Disease
Abstract
The mineralocorticoid hormone aldosterone regulates sodium and potassium homeostasis but also adversely modulates the maladaptive process of cardiac adverse remodeling post-myocardial infarction. Through activation of its mineralocorticoid receptor (MR), a classic steroid hormone receptor/transcription factor, aldosterone promotes inflammation and fibrosis of the heart, the vasculature, and the kidneys. This is why MR antagonists reduce morbidity and mortality of heart disease patients and are part of the mainstay pharmacotherapy of advanced human heart failure. A plethora of animal studies using cell type⁻specific targeting of the MR gene have established the importance of MR signaling and function in cardiac myocytes, vascular endothelial and smooth muscle cells, renal cells, and macrophages. In terms of its signaling properties, the MR is distinct from nuclear receptors in that it has, in reality, two physiological hormonal agonists: not only aldosterone but also cortisol. In fact, in several tissues, including in the myocardium, cortisol is the primary hormone activating the MR. There is a considerable amount of evidence indicating that the effects of the MR in each tissue expressing it depend on tissue- and ligand-specific engagement of molecular co-regulators that either activate or suppress its transcriptional activity. Identification of these co-regulators for every ligand that interacts with the MR in the heart (and in other tissues) is of utmost importance therapeutically, since it can not only help elucidate fully the pathophysiological ramifications of the cardiac MR's actions, but also help design and develop novel better MR antagonist drugs for heart disease therapy. Among the various proteins the MR interacts with are molecules involved in cardiac G protein-coupled receptor (GPCR) signaling. This results in a significant amount of crosstalk between GPCRs and the MR, which can affect the latter's activity dramatically in the heart and in other cardiovascular tissues. This review summarizes the current experimental evidence for this GPCR-MR crosstalk in the heart and discusses its pathophysiological implications for cardiac adverse remodeling as well as for heart disease therapy. Novel findings revealing non-conventional roles of GPCR signaling molecules, specifically of GPCR-kinase (GRK)-5, in cardiac MR regulation are also highlighted.
Keywords: G protein-coupled receptor (GPCR); GPCR-kinase (GRK); adverse remodeling; aldosterone; cardiac myocyte; crosstalk; heart failure; inflammation; mineralocorticoid receptor; myocardial infarction; oxidative stress; signal transduction.
Conflict of interest statement
The authors declare no conflict of interest related to this publication.
Figures
Similar articles
-
Antagonistic Roles of GRK2 and GRK5 in Cardiac Aldosterone Signaling Reveal GRK5-Mediated Cardioprotection via Mineralocorticoid Receptor Inhibition.Int J Mol Sci. 2020 Apr 20;21(8):2868. doi: 10.3390/ijms21082868. Int J Mol Sci. 2020. PMID: 32326036 Free PMC article.
-
Impact of Aldosterone on the Failing Myocardium: Insights from Mitochondria and Adrenergic Receptors Signaling and Function.Cells. 2021 Jun 19;10(6):1552. doi: 10.3390/cells10061552. Cells. 2021. PMID: 34205363 Free PMC article. Review.
-
Mineralocorticoids in the heart and vasculature: new insights for old hormones.Annu Rev Pharmacol Toxicol. 2015;55:289-312. doi: 10.1146/annurev-pharmtox-010814-124302. Epub 2014 Sep 10. Annu Rev Pharmacol Toxicol. 2015. PMID: 25251996 Review.
-
Mechanisms of mineralocorticoid receptor-mediated cardiac fibrosis and vascular inflammation.Curr Opin Nephrol Hypertens. 2008 Mar;17(2):174-80. doi: 10.1097/MNH.0b013e3282f56854. Curr Opin Nephrol Hypertens. 2008. PMID: 18277151 Review.
-
Mineralocorticoid receptor actions in cardiovascular development and disease.Essays Biochem. 2021 Dec 17;65(6):901-911. doi: 10.1042/EBC20210006. Essays Biochem. 2021. PMID: 34414409 Review.
Cited by
-
GPER and Testicular Germ Cell Cancer.Front Endocrinol (Lausanne). 2021 Jan 26;11:600404. doi: 10.3389/fendo.2020.600404. eCollection 2020. Front Endocrinol (Lausanne). 2021. PMID: 33574796 Free PMC article. Review.
-
Correlation of functional and radioligand binding characteristics of GPER ligands confirming aldosterone as a GPER agonist.Pharmacol Res Perspect. 2022 Oct;10(5):e00995. doi: 10.1002/prp2.995. Pharmacol Res Perspect. 2022. PMID: 36065843 Free PMC article.
-
G Protein-Coupled Estrogen Receptor: A Potential Therapeutic Target in Cancer.Front Endocrinol (Lausanne). 2019 Oct 25;10:725. doi: 10.3389/fendo.2019.00725. eCollection 2019. Front Endocrinol (Lausanne). 2019. PMID: 31708873 Free PMC article. Review.
-
Mineralocorticoid Receptor Antagonists in Diabetic Kidney Disease.Front Pharmacol. 2021 Oct 28;12:754239. doi: 10.3389/fphar.2021.754239. eCollection 2021. Front Pharmacol. 2021. PMID: 34790127 Free PMC article. Review.
-
Impact of Mineralocorticoid Receptor Gene NR3C2 on the Prediction of Functional Classification of Left Ventricular Remodeling and Arrhythmia after Acute Myocardial Infarction.Int J Environ Res Public Health. 2022 Dec 20;20(1):12. doi: 10.3390/ijerph20010012. Int J Environ Res Public Health. 2022. PMID: 36612333 Free PMC article.
References
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Medical