The Mineralocorticoid Receptor in Heart
2011; Lippincott Williams & Wilkins; Volume: 57; Issue: 4 Linguagem: Inglês
10.1161/hypertensionaha.110.164962
ISSN1524-4563
AutoresFrédéric Jaisser, Bernard Swynghedauw, Claude Delcayre,
Tópico(s)Advanced Thermodynamics and Statistical Mechanics
ResumoHomeHypertensionVol. 57, No. 4The Mineralocorticoid Receptor in Heart Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBThe Mineralocorticoid Receptor in HeartDifferent Effects in Different Cells Frederic Jaisser, Bernard Swynghedauw and Claude Delcayre Frederic JaisserFrederic Jaisser From the Institut National de la Santé et de la Recherche Médicale U872 (F.J.), Centre de Recherche des Cordeliers, Paris, France; Institut National de la Santé et de la Recherche Médicale U942 (B.S., C.D.), Hopital Lariboisiere, Paris, France. , Bernard SwynghedauwBernard Swynghedauw From the Institut National de la Santé et de la Recherche Médicale U872 (F.J.), Centre de Recherche des Cordeliers, Paris, France; Institut National de la Santé et de la Recherche Médicale U942 (B.S., C.D.), Hopital Lariboisiere, Paris, France. and Claude DelcayreClaude Delcayre From the Institut National de la Santé et de la Recherche Médicale U872 (F.J.), Centre de Recherche des Cordeliers, Paris, France; Institut National de la Santé et de la Recherche Médicale U942 (B.S., C.D.), Hopital Lariboisiere, Paris, France. Originally published14 Feb 2011https://doi.org/10.1161/HYPERTENSIONAHA.110.164962Hypertension. 2011;57:679–680Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2011: Previous Version 1 See related article, pp 746–754The mineralocorticoid receptor (MR) antagonists (MRAs) spironolactone and eplerenone have beneficial effects in patients with heart failure (HF) or left ventricular dysfunction.1 This underscores the major role of an inadequate hormonal stimulation leading to MR activation in HF. However, the actions of MRAs are complex and several questions remained unsolved. Which biochemical pathways are activated by the hormone that binds the cardiac MR? Which hormone binds the cardiac MR? In which pathological settings are the MRAs most appropriately used?The MR is the intracellular receptor of aldosterone. The hormone-receptor complex binds to a specific DNA sequence and triggers the transcription of target genes. In epithelial cells, the induced genes are mostly involved in the control of sodium reabsorption. However, the link between the beneficial effects of MRA in HF and these actions related to sodium control are unclear. Spironolactone is efficient in HF patients at a subhypotensive dose that likely did not involve diuretic effects. This suggests that spironolactone action in this setting was, at least in part, directed toward the MR of nonepithelial cells.Disappropriately increased levels of aldosterone in plasma are associated with inflammation and fibrosis in heart and blood vessels. Indeed, improved outcomes with spironolactone in HF have been linked to the antifibrotic effects of spironolactone. The MR is expressed in several cardiac cell types, cardiomyocytes and fibroblasts, and in vascular endothelial and smooth muscle cells, raising the question of its function in these tissues. Genetic technologies in mice have allowed selective deletion or overexpression of MR in different cardiac cell types. These tricky experimentations give novel and interesting informations.The study published in this issue of Hypertension by Lother et al2 compared the response to a chronic severe pressure overload in 2 mouse models with cell-specific deletion of MR in cardiomyocytes or in fibroblasts. They observed that MR deletion in cardiomyocytes prevented the left ventricular dilatation and failure observed in control mice after pressure overload. Left ventricular inner diastolic diameter and wall tension increased in control mice after pressure overload but remained unchanged in mice with cardiomyocyte MR deletion. This is consistent with previous results showing that eplerenone delayed the transition from compensated cardiac hypertrophy to dilatation and failure in mice.3 Similarly, neither eplerenone3 nor cardiomyocyte-specific MR ablation in the study by Lother et al2 prevented cardiac hypertrophy after pressure overload.The results of this loss-of-function experiment may be compared with the mirror experiment, the effect of MR gain of function. The conditional MR-specific overexpression in cardiomyocytes induces a cardiac ion channel remodeling, severe ventricular arrhythmias, and a high rate of death.4 This finding is possibly related to the increased rate of atrial fibrillation found in patients with hyperaldosteronism.5 More surprising at first glance is the response to aortic constriction of mice with MR deletion in fibroblasts: they are not protected from the cardiac fibrosis, which is observed in control mice.2 However, this observation is consistent with findings from macrophage-specific MR deletion studies. Indeed, MR deletion in macrophages reduced cardiac oxidative stress and inflammation, as well as cardiac fibrosis induced by NG-nitro-l-arginine methyl ester/ angiotensin II6 or deoxycorticosterone acetate/salt treatment.7 Importantly, these inflammatory-type cells express the MR and are almost never found in normal hearts. However, a severe vascular stress triggers the release of cytokines like monocyte chemoattractant protein 1 that induce the infiltration of macrophages in the heart. In these experiments, MR knockout in macrophages prevented the cardiac fibrosis, although the cardiac recruitment of these cells was not prevented.6–7 These observations indicate that an MR signaling in macrophages is required to elicit the cardiac fibrosis associated with severe hemodynamic or hormonal challenges, and that it is mainly of extracardiac origin. This is in agreement with other results where cardiomyocyte-specific MR deletion2 or overexpression4 did not induce fibrosis.Now, the scheme becomes more clear (Figure). There are (at least) 2 major functional pathways that may be activated by the MR, depending on the cell type that bears MR. The perivascular inflammatory phenotype that is seen in conditions of severe hemodynamic or hormonal stress is of vascular origin, and it is secondary to the activation and cardiac infiltration of macrophages. The macrophage MR thus plays a prominent role in cardiac fibrosis. On the other hand, the MR of cardiomyocytes serves functions that are specifically related to the properties of the cardiac muscle but not to the cardiac hypertrophic response. The globally negative effects that result from MR activation in cardiomyocytes remain an open question: why should such a harmful receptor be present in heart? One may hypothesize that this MR has still-unknown functions in the normal heart. In this view, the observation that the cardiomyocyte MR-deficient mice had a mild cardiac hypertrophy at baseline likely contributing to protection of heart against pressure overload2 suggests a role for MR in the control of cardiomyocyte growth. Future studies using specific overexpression of MR in other cardiac or vascular cell types could help to solve this question.Download figureDownload PowerPointFigure. Diagram depicting the effects of MR blockade or MR gene deletion in mice on the cardiac response to stress. This diagram summarizes the main results from the studies referenced in parentheses. Top row, Imposition of a stress (aortic stenosis, NG-nitro-l-arginine methyl ester/angiotensin II, or deoxycorticosterone acetate/salt) induces well-described structural and functional alterations in heart. Bottom rows, MR blockade by eplerenone improves parameters linked to the muscular (left ventricular dysfunction and dilatation) and to the nonmuscular (oxidative stress, inflammation, and fibrosis) compartments. Cell-specific deletion of MR shows that selective improvement of the muscular or nonmuscular compartments depends on different MR-containing cell types. Ox. stress indicates oxidative stress; c-myocyte, cardiomyocyte; N.D., not determined.The hormone that activates the MR in cardiomyocytes is a matter of debate that cannot be fully discussed here. MR binds mineralocorticoids and glucocorticoids with equal affinity. In cardiomyocytes or vascular smooth muscle cells where the 11β-hydroxysteroid dehydrogenase 2 activity (which protects the MR from glucocorticoids) is low or even absent, the very high concentration of glucocorticoids relative to aldosterone gives them a theoretical advantage to occupy the MR. Nevertheless, experimental results show that in vivo aldosterone has actions in cardiomyocytes that alter the regulation of the ryanodine receptor.8 The transactivation efficacy of the hormone-MR complexes depends on binding, hormone-receptor stability, and interactions of cofactors. Interestingly, the aldosterone-MR complex is more stable and is 200-fold more active for transactivation than the glucocorticoid-MR complex, opening the possibility of a balance between aldosterone and glucocorticoids for MR activation. It would, therefore, be interesting to identify the specific MR signaling pathway according to the ligand that activates the MR in vivo. Transgenic models with targeted overexpression of MR and administration of glucocorticoids or aldosterone could help to address this issue. This may have important consequences for the use of MRAs versus aldosterone-synthase inhibitors.Cardiac expression of MR is increased in hypertension, atrial fibrillation, myocardial infarction, and diastolic HF. Therefore, the MR activation level could be increased even with normal levels of aldosterone and glucocorticoids. Moreover, an aldosterone-independent activation of the MR is another intriguing possibility. This is suggested by observations in the kidney, where the MR may be activated by rac-1 in the absence of aldosterone, and by a previous observation that MR is activated by angiotensin II in cultured smooth muscle cells. Indeed, angiotensin II and aldosterone are chronically increased in cardiovascular diseases. Cross-talks exist between the pathways of angiotensin and aldosterone that may potentiate their own actions.9 These effects deserve additional studies and support the concept of a combined inhibition of an angiotensin receptor and MR in cardiovascular disease. MRAs are underused in HF,10 and the recent results discussed above suggest that MRAs should be more widely used to antagonize the increased MR activation seen in several pathologies, including HF.Sources of FundingThis work was supported by Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, and Fondation de France.DisclosuresNone.FootnotesThe opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.Correspondence to Claude Delcayre, INSERM U942, Hopital Lariboisière, 41 Boulevard de la Chapelle, 75475 Paris Cedex 10, France. E-mail Claude.[email protected]frReferences1. Greenberg B, Zannad F, Pitt B. Role of aldosterone blockade for treatment of heart failure and post-acute myocardial infarction. Am J Cardiol. 2006; 97:34F–40F.CrossrefMedlineGoogle Scholar2. Lother A, Berger S, Gilsbach R, Rösner S, Ecke A, Barreto F, Bauersachs J, Schütz G, Hein L. Ablation of mineralocorticoid receptors in myocytes but not in fibroblasts preserves cardiac function. Hypertension. 2011; 57:746–754.LinkGoogle Scholar3. Kuster GM, Kotlyar E, Rude MK, Siwik DA, Liao R, Colucci WS, Sam F. Mineralocorticoid receptor inhibition ameliorates the transition to myocardial failure and decreases oxidative stress and inflammation in mice with chronic pressure overload. Circulation. 2005; 111:420–427.LinkGoogle Scholar4. Ouvrard-Pascaud A, Sainte-Marie Y, Benitah JP, Perrier R, Soukaseum C, Cat AN, Royer A, Le Quang K, Charpentier F, Demolombe S, Mechta-Grigoriou F, Beggah AT, Maison-Blanche P, Oblin ME, Delcayre C, Fishman GI, Farman N, Escoubet B, Jaisser F. Conditional mineralocorticoid receptor expression in the heart leads to life-threatening arrhythmias. Circulation. 2005; 111:3025–3033.LinkGoogle Scholar5. Milliez P, Girerd X, Plouin PF, Blacher J, Safar ME, Mourad JJ. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol. 2005; 45:1243–1248.CrossrefMedlineGoogle Scholar6. Usher MG, Duan SZ, Ivaschenko CY, Frieler RA, Berger S, Schutz G, Lumeng CN, Mortensen RM. Myeloid mineralocorticoid receptor controls macrophage polarization and cardiovascular hypertrophy and remodeling in mice. J Clin Invest. 2010; 120:3350–3364.CrossrefMedlineGoogle Scholar7. Rickard AJ, Morgan J, Tesch G, Funder JW, Fuller PJ, Young MJ. Deletion of mineralocorticoid receptors from macrophages protects against deoxycorticosterone/salt-induced cardiac fibrosis and increased blood pressure. Hypertension. 2009; 54:537–543.LinkGoogle Scholar8. Gomez AM, Rueda A, Sainte-Marie Y, Pereira L, Zissimopoulos S, Zhu X, Schaub R, Perrier E, Perrier R, Latouche C, Richard S, Picot MC, Jaisser F, Lai FA, Valdivia HH, Benitah JP. Mineralocorticoid modulation of cardiac ryanodine receptor activity is associated with downregulation of FK506-binding proteins. Circulation. 2009; 119:2179–2187.LinkGoogle Scholar9. Lemarie CA, Paradis P, Schiffrin EL. New insights on signaling cascades induced by cross-talk between angiotensin II and aldosterone. J Mol Med. 2008; 86:673–678.CrossrefMedlineGoogle Scholar10. Samuel JL, Delcayre C. Heart failure: aldosterone antagonists are underused by clinicians. Nat Rev Cardiol. 2010; 7:125–127.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Brooks D, Garza A, Caliskan Guzelce E, Gholami S, Treesaranuwattana T, Maris S, Ranjit S, Tay C, Lee J, Romero J, Adler G, Pojoga L and Williams G (2020) mTORC1 Deficiency Modifies Volume Homeostatic Responses to Dietary Sodium in a Sex-Specific Manner, Endocrinology, 10.1210/endocr/bqaa041, 161:5, Online publication date: 1-May-2020. Abdel Ghafar M (2020) An overview of the classical and tissue-derived renin-angiotensin-aldosterone system and its genetic polymorphisms in essential hypertension, Steroids, 10.1016/j.steroids.2020.108701, 163, (108701), Online publication date: 1-Nov-2020. Samuel J and Delcayre C (2017) La fibrose cardiaque, Bulletin de l'Académie Nationale de Médecine, 10.1016/S0001-4079(19)30460-1, 201:4-6, (775-784), Online publication date: 1-Apr-2017. Jaisser F, Farman N and Touyz R (2015) Emerging Roles of the Mineralocorticoid Receptor in Pathology: Toward New Paradigms in Clinical Pharmacology, Pharmacological Reviews, 10.1124/pr.115.011106, 68:1, (49-75), Online publication date: 1-Jan-2016. Bauersachs J, Jaisser F and Toto R (2014) Mineralocorticoid Receptor Activation and Mineralocorticoid Receptor Antagonist Treatment in Cardiac and Renal Diseases, Hypertension, 65:2, (257-263), Online publication date: 1-Feb-2015. 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Herrada A, Campino C, Amador C, Michea L, Fardella C and Kalergis A (2011) Aldosterone as a modulator of immunity, Journal of Hypertension, 10.1097/HJH.0b013e32834a4c75, 29:9, (1684-1692), Online publication date: 1-Sep-2011. Bernardi J, Aromolaran K, Zhu H and Aromolaran A (2021) Circadian Mechanisms: Cardiac Ion Channel Remodeling and Arrhythmias, Frontiers in Physiology, 10.3389/fphys.2020.611860, 11 April 2011Vol 57, Issue 4 Advertisement Article InformationMetrics © 2011 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.110.164962PMID: 21321302 Originally publishedFebruary 14, 2011 PDF download Advertisement SubjectsCardiorenal SyndromeMyocardial Biology
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