Endothelial Cell Mineralocorticoid Receptors
2014; Lippincott Williams & Wilkins; Volume: 63; Issue: 5 Linguagem: Inglês
10.1161/hypertensionaha.114.01997
ISSN1524-4563
AutoresIris Z. Jaffe, Frédéric Jaisser,
Tópico(s)Sodium Intake and Health
ResumoHomeHypertensionVol. 63, No. 5Endothelial Cell Mineralocorticoid Receptors Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBEndothelial Cell Mineralocorticoid ReceptorsTurning Cardiovascular Risk Factors Into Cardiovascular Dysfunction Iris Z. Jaffe and Frédéric Jaisser Iris Z. JaffeIris Z. Jaffe From Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (I.Z.J.); and INSERM U1138, Cordeliers Research Center, Paris, France (F.J.). and Frédéric JaisserFrédéric Jaisser From Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (I.Z.J.); and INSERM U1138, Cordeliers Research Center, Paris, France (F.J.). Originally published24 Feb 2014https://doi.org/10.1161/HYPERTENSIONAHA.114.01997Hypertension. 2014;63:915–917Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2014: Previous Version 1 See related article, pp 1033–1040Clinically, mineralocorticoid receptor (MR) antagonists are widely prescribed for the treatment of hypertension and heart failure because of their diuretic action in aldosterone-sensitive distal nephron. Clinical trials of MR antagonism in patients with various degrees of heart failure severity have also demonstrated a pronounced reduction of cardiovascular mortality in MR antagonist–treated patients.1 The underlying mechanisms of these cardiovascular benefits are still debated and are probably diverse. Potential beneficial effects of MR antagonism on extracellular matrix remodeling, arrhythmia susceptibility, coronary flow reserve, cardiovascular inflammation, and vascular function have all been suggested. Indeed, the vasculature has been recently highlighted as a primary target of aldosterone and MR antagonists. MR is expressed in human vascular endothelial cells (ECs) and smooth muscle cells as is the 11β-HSD2 enzyme that allows for selective aldosterone versus cortisol activation of MR. The effects of MR activation on vascular reactivity in healthy humans remains controversial because of conflicting results from clinical studies with many demonstrating a constrictive response and some showing vascular relaxation.2 Discrepancies may be due to differences in the vascular health of study participants as well as differences in study design. However, when patients with underlying cardiovascular diseases are studied, the data are consistent with MR activation promoting increased systemic vascular resistance and reduced forearm blood flow and MR antagonism improving endothelium-dependent vasodilatation, independent of changes in blood pressure. The aggregate of data supports that, in healthy vessels, acute MR activation may evoke endothelium-dependent, NO-mediated vasodilatation, whereas, in the presence of endothelial dysfunction, vascular injury, or high vascular oxidative stress (as in patients with cardiovascular risk factors or heart failure), MR activation promotes vasoconstriction.2Recently, 2 experimental studies, using a mouse model with targeted inactivation of MR in the endothelium, have attempted to address this controversy more directly.3,4 Both studies demonstrate that, in a healthy animal, EC-specific deletion of the MR has no effect on systemic blood pressure or contractile or relaxation function of mesenteric resistance vessel, indicating that endothelial MR does not contribute substantially to these parameters in the absence of disease stimuli. However, both studies reveal that, in the setting of cardiovascular risk factors, vascular function is negatively affected by the presence of MR in ECs. Diet-induced obesity or aldosterone infusion was used in the Schäfer et al study,3 whereas mineralocorticoid/salt-induced hypertension was used to induce cardiovascular dysfunction in the Rickard et al study.4 A decline in endothelium-dependent relaxation to acetylcholine caused by the induction of obesity or aldosterone infusion was blunted in the aortae of obese mice lacking EC MR, mimicking the beneficial effect of chronic treatment with eplerenone, a specific MR antagonist.3 This was independent from proinflammatory changes in aortic ECs. EC MR was also mandatory for mineralocorticoid/salt-induced hypertension to induce endothelial dysfunction.4 Conversely, a chronic increase of MR expression specifically in the endothelium has been shown to increase the vasoactive response to angiotensin II and endothelin 1, as well as basal blood pressure and angiotensin II/endothelin 1–induced hypertension.5 The mechanisms remain to be determined, but EC MR likely contributes to vascular oxidative stress and NO production as 1 mechanism that regulates vascular contraction and relaxation in the setting of cardiovascular risk factors. Indeed, EC deletion of MR prevented aldosterone induction of NADPH oxidase subunit p22phox and COX1 in ECs.3 This suggests that EC MR is necessary for aldosterone to induce oxidative stress and associated vascular dysfunction, at least in the setting of obesity-induced vascular disease.In the present issue, Rickard et al4 provide compelling evidence that MR expression in the endothelium is required for mineralocorticoid/salt hypertension to induce cardiac fibrosis. This study, therefore, provides new insights into the crucial role of MR activation in the endothelium to sustain the inflammatory process induced by mineralocarticoid/salt challenge leading to the stimulation of extracellular matrix remodeling in the heart. The underlying mechanisms remain to be completely elucidated, but it is suggested that protection could be because of the absence of macrophage invasion into the cardiac tissue in EC MR–deficient mice. EC MR has been found to regulate endothelial intercellular adhesion molecule-1 expression to promote leukocyte EC adhesion, a necessary step for cardiovascular inflammation.6 Indeed, EC MR deletion attenuated the increase in cardiac intercellular adhesion molecule-1 expression induced by DOCA-salt and prevented cardiac inflammation and cardiac fibrosis. Of note, 1 limitation of these models is the use of the Tie2/Tek promoter to drive the expression of Cre recombinase. Indeed, the Tie2/Tek promoter sequence has been previously found to target not only ECs but also myeloid cells, resulting in decreased macrophage MR expression when used with MR recombinant mice.3 Thus, it cannot be excluded that the prevention of cardiac remodeling also relies on the deletion of macrophage MR in the DOCA-salt model because macrophage MR has already been found to contribute to proinflammatory macrophage phenotype that is necessary for cardiac and vascular fibrosis.7,8 It is possible that both blunted macrophage infiltration and decreased macrophage MR activation may participate to decrease cardiac remodeling induced by mineralocarticoid/salt challenge in this EC MR knockout model.In addition to the contribution to cardiovascular inflammation by the regulation of adhesion molecules or impaired relaxation related to oxidative stress, EC MR might contribute to vascular function by other mechanisms that remain to be explored. Local aldosterone infusion into the eye induced a major vasodilation of retinal choroid vascular bed, mimicking a vision-threatening disease called central serous chorioretinitis, providing the rationale for a spectacular benefit of eplerenone in these patients.9 The underlying mechanism relied on the increased activity of endothelial KCa2.3 potassium ion channel involved in endothelium-dependent vasodilation.9 Endothelial MR also participates to endothelium stiffening via the modulation of epithelial sodium channel subunits expression/activity in the endothelium.10 Recent work revealed that aldosterone unexpectedly induced the downregulation of thrombin generation by the endothelium, an effect caused by an enhancement of thrombomodulin-mediated protein C activation. This was blunted by drospirenone, a contraceptive with potent MR antagonist property associated with increased thrombosis in healthy women, highlighting a novel role of endothelial MR with potential therapeutic issues.11In conclusion, the data presented by Rickard et al4 in the current issue of Hypertension support a model in which EC MR may be beneficial or neutral (Figure) in healthy vasculature (no effect on blood pressure and neutral or beneficial effects in terms of endothelial function or endothelial-dependent vasodilation) while playing a crucial role in the setting of cardiovascular risk factors, including obesity, hypertension, and other likely risk factors that remain to be tested. EC MR activation by aldosterone (or other activators such as corticosteroids in the eye) seems to mediate at least some of the detrimental effects of these risk factors on vascular function and cardiovascular fibrosis. These findings might help explain the substantial benefits of MR inhibition in patients with heart failure. Whether endothelial MR also participates to the pathophysiology of other diseases such as atherosclerosis, sepsis, tissue ischemia including myocardial infarction, stroke, or renal ischemia remains to be explored. Because the use of MR antagonists could be limited by their side effects (hyperkalemia, gynecomastia), further exploration of molecular mechanisms by which EC MR mediates the detrimental effects of known cardiovascular risk factors could identify novel treatment strategies that retain the substantial cardiovascular benefits of MR antagonists without the limiting side effects.Download figureDownload PowerPointFigure. Model highlighting targets modulated by mineralocorticoid receptor activation in the endothelium and physiological and pathophysiological consequences in healthy individuals and in the presence of risk factors. EC indicates endothelial cell; ENaC, epithelial sodium channel; eNOS, endothelial nitric oxide synthase; ICAM, intercellular adhesion molecule; MR, mineralocorticoid receptor; ROS, reactive oxygen species; and SMC, smooth muscle cell.Sources of FundingThis work was supported by Institut National de la Sante et de la Recherche Medicale, grants from the Agence Nationale pour la Recherche (ANR09-BLAN-0156-01), and a fellowship from the Philippe Foundation to F.J., and grants from the National Institutes of Health (HL095590-05) and the American Heart Association (GIA0855920D) to I.Z.J.DisclosuresNone.FootnotesThe opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.Correspondence to Frédéric Jaisser, Centre de Recherche des Cordeliers, INSERM U1138 Team 1, 15 rue de l'Ecole de Médecine, 75270 Paris cedex 06, France. E-mail [email protected]References1. Zannad F, Gattis Stough W, Rossignol P, et al. Mineralocorticoid receptor antagonists for heart failure with reduced ejection fraction: integrating evidence into clinical practice.Eur Heart J. 2012; 33:2782–2795.CrossrefMedlineGoogle Scholar2. McCurley A, Jaffe IZ. Mineralocorticoid receptors in vascular function and disease.Mol Cell Endocrinol. 2012; 350:256–265.CrossrefMedlineGoogle Scholar3. Schäfer N, Lohmann C, Winnik S, van Tits LJ, Miranda MX, Vergopoulos A, Ruschitzka F, Nussberger J, Berger S, Lüscher TF, Verrey F, Matter CM. Endothelial mineralocorticoid receptor activation mediates endothelial dysfunction in diet-induced obesity.Eur Heart J. 2013; 34:3515–3524.CrossrefMedlineGoogle Scholar4. Rickard AJ, Morgan J, Chrissobolis S, Miller AA, Sobey CG, Young MJ. Endothelial cell mineralocorticoid receptors regulate deoxycorticosterone/salt-mediated cardiac remodeling and vascular reactivity but not blood pressure.Hypertension2014; 63:1033–1040.LinkGoogle Scholar5. Nguyen Dinh Cat A, Griol-Charhbili V, Loufrani L, Labat C, Benjamin L, Farman N, Lacolley P, Henrion D, Jaisser F. The endothelial mineralocorticoid receptor regulates vasoconstrictor tone and blood pressure.FASEB J. 2010; 24:2454–2463.CrossrefMedlineGoogle Scholar6. Caprio M, Newfell BG, la Sala A, Baur W, Fabbri A, Rosano G, Mendelsohn ME, Jaffe IZ. Functional mineralocorticoid receptors in human vascular endothelial cells regulate intercellular adhesion molecule-1 expression and promote leukocyte adhesion.Circ Res. 2008; 102:1359–1367.LinkGoogle 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. Usher MG, Duan SZ, Ivaschenko CY, Frieler RA, Berger S, Schütz 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 Scholar9. Zhao M, Célérier I, Bousquet E, Jeanny JC, Jonet L, Savoldelli M, Offret O, Curan A, Farman N, Jaisser F, Behar-Cohen F. Mineralocorticoid receptor is involved in rat and human ocular chorioretinopathy.J Clin Invest. 2012; 122:2672–2679.CrossrefMedlineGoogle Scholar10. Jeggle P, Callies C, Tarjus A, Fassot C, Fels J, Oberleithner H, Jaisser F, Kusche-Vihrog K. Epithelial sodium channel stiffens the vascular endothelium in vitro and in Liddle mice.Hypertension. 2013; 61:1053–1059.LinkGoogle Scholar11. Lagrange J, Li Z, Fassot C, Bourhim M, Louis H, Nguyen Dinh Cat A, Parlakian A, Wahl D, Lacolley P, Jaisser F, Regnault V. Endothelial mineralocorticoid receptor activation enhances endothelial protein c receptor and decreases vascular thrombosis in mice [published online ahead of print January 22, 2014].FASEB J. doi: 10.1096/fj.13-238188. http://www.fasebj.org/content/early/2014/01/22/fj.13-238188.full.pdf+html. Accessed February 18, 2014.Google Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Salazar-Enciso R, Guerrero-Hernández A, Gómez A, Benitah J and Rueda A (2022) Aldosterone-Induced Sarco/Endoplasmic Reticulum Ca2+ Pump Upregulation Counterbalances Cav1.2-Mediated Ca2+ Influx in Mesenteric Arteries, Frontiers in Physiology, 10.3389/fphys.2022.834220, 13 Ogata H, Yamazaki Y, Tezuka Y, Gao X, Omata K, Ono Y, Kawasaki Y, Tanaka T, Nagano H, Wada N, Oki Y, Ikeya A, Oki K, Takeda Y, Kometani M, Kageyama K, Terui K, Gomez-Sanchez C, Liu S, Morimoto R, Joh K, Sato H, Miyazaki M, Ito A, Arai Y, Nakamura Y, Ito S, Satoh F and Sasano H (2021) Renal Injuries in Primary Aldosteronism: Quantitative Histopathological Analysis of 19 Patients With Primary Adosteronism, Hypertension, 78:2, (411-421), Online publication date: 1-Aug-2021. Chambers L and Dorrance A (2020) Regulation of ion channels in the microcirculation by mineralocorticoid receptor activation Ion Channels and Calcium Signaling in the Microcirculation, 10.1016/bs.ctm.2020.02.001, (151-185), . Aroor A, Jia G and Sowers J (2018) Cellular mechanisms underlying obesity-induced arterial stiffness, American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 10.1152/ajpregu.00235.2016, 314:3, (R387-R398), Online publication date: 1-Mar-2018. Verheyen N, Grübler M, Meinitzer A, Trummer C, Schwetz V, Amrein K, Dimai H, März W, Catena C, von Lewinski D, Voelkl J, Alesutan I, Fahrleitner-Pammer A, Brussee H, Pilz S and Tomaschitz A (2017) Effect of eplerenone on markers of bone turnover in patients with primary hyperparathyroidism – The randomized, placebo-controlled EPATH trial, Bone, 10.1016/j.bone.2017.08.030, 105, (212-217), Online publication date: 1-Dec-2017. DuPont J and Jaffe I 30 YEARS OF THE MINERALOCORTICOID RECEPTOR: The role of the mineralocorticoid receptor in the vasculature, Journal of Endocrinology, 10.1530/JOE-17-0009, 234:1, (T67-T82) Tesch G and Young M (2017) Mineralocorticoid Receptor Signaling as a Therapeutic Target for Renal and Cardiac Fibrosis, Frontiers in Pharmacology, 10.3389/fphar.2017.00313, 8 Shibata S, Ishizawa K and Uchida S (2016) Mineralocorticoid receptor as a therapeutic target in chronic kidney disease and hypertension, Hypertension Research, 10.1038/hr.2016.137, 40:3, (221-225), Online publication date: 1-Mar-2017. Lother A, Fürst D, Bergemann S, Gilsbach R, Grahammer F, Huber T, Hilgendorf I, Bode C, Moser M and Hein L (2015) Deoxycorticosterone Acetate/Salt–Induced Cardiac But Not Renal Injury Is Mediated By Endothelial Mineralocorticoid Receptors Independently From Blood Pressure, Hypertension, 67:1, (130-138), Online publication date: 1-Jan-2016. Jeggle P, Hofschröer V, Maase M, Bertog M and Kusche‐Vihrog K (2015) Aldosterone synthase knockout mouse as a model for sodium‐induced endothelial sodium channel up‐regulation in vascular endothelium, The FASEB Journal, 10.1096/fj.14-259606, 30:1, (45-53), Online publication date: 1-Jan-2016. Hwang M, Yoo J, Luttrell M, Kim H, Meade T, English M, Talcott S, Jaffe I and Christou D (2016) Acute effect of mineralocorticoid receptor antagonism on vascular function in healthy older adults, Experimental Gerontology, 10.1016/j.exger.2015.11.017, 73, (86-94), Online publication date: 1-Jan-2016. Jia G, Habibi J, DeMarco V, Martinez-Lemus L, Ma L, Whaley-Connell A, Aroor A, Domeier T, Zhu Y, Meininger G, Barrett Mueller K, Jaffe I and Sowers J (2015) Endothelial Mineralocorticoid Receptor Deletion Prevents Diet-Induced Cardiac Diastolic Dysfunction in Females, Hypertension, 66:6, (1159-1167), Online publication date: 1-Dec-2015.Barrett Mueller K, Bender S, Hong K, Yang Y, Aronovitz M, Jaisser F, Hill M and Jaffe I (2015) Endothelial Mineralocorticoid Receptors Differentially Contribute to Coronary and Mesenteric Vascular Function Without Modulating Blood Pressure, Hypertension, 66:5, (988-997), Online publication date: 1-Nov-2015. Gomez-Sanchez E (2014) Brain mineralocorticoid receptors in cognition and cardiovascular homeostasis, Steroids, 10.1016/j.steroids.2014.08.014, 91, (20-31), Online publication date: 1-Dec-2014. May 2014Vol 63, Issue 5 Advertisement Article InformationMetrics © 2014 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.114.01997PMID: 24566083 Originally publishedFebruary 24, 2014 PDF download Advertisement SubjectsCatheter Ablation and Implantable Cardioverter-Defibrillator
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