Mineralocorticoid Receptors
2020; Lippincott Williams & Wilkins; Volume: 127; Issue: 3 Linguagem: Romeno
10.1161/circresaha.120.317424
ISSN1524-4571
Autores Tópico(s)Adrenal Hormones and Disorders
ResumoHomeCirculation ResearchVol. 127, No. 3Mineralocorticoid Receptors Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBMineralocorticoid ReceptorsMaster Regulators of Extracellular Matrix Remodeling Achim Lother Achim LotherAchim Lother Correspondence to: Achim Lother, Department of Cardiology and Angiology I, Heart Center Freiburg University, Hugstetter Str. 55, 79106 Freiburg, Germany. Email E-mail Address: [email protected] https://orcid.org/0000-0001-9107-5558 From the Department of Cardiology and Angiology I, Faculty of Medicine, Heart Center Freiburg University, University of Freiburg, Germany (A.L.) Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Germany (A.L.). Originally published16 Jul 2020https://doi.org/10.1161/CIRCRESAHA.120.317424Circulation Research. 2020;127:354–356This article is a commentary on the followingA New Role for the Aldosterone/Mineralocorticoid Receptor Pathway in the Development of Mitral Valve ProlapseThe mineralocorticoid receptor (MR) is a ligand-activated nuclear transcription factor. Aldosterone, the main mineralocorticoid hormone, is produced by zona glomerulosa cells in the adrenal cortex as part of the renin-angiotensin-aldosterone-system.1 Upon ligand activation, MR translocates into the nucleus and binds to enhancer or promotor regions, controlling the expression of its target genes. The classical role of MR is to maintain blood pressure and salt-water-homeostasis by regulating the expression of sodium-handling proteins in renal epithelial cells.1 However, since a number of large clinical trials during the past 2 decades demonstrated a striking benefit of MR antagonists on mortality and morbidity of patients with heart failure, aldosterone and MR are now considered as key drivers of cardiovascular disease.1–3 Experimental studies demonstrated beneficial effects of MR antagonists on oxidative stress, apoptosis, inflammation, fibrosis, cardiac myocyte hypertrophy, endothelial dysfunction, and electrical remodeling in cardiac disease models (Figure).3Article, see p e80Download figureDownload PowerPointFigure. The mineralocorticoid receptor as regulator of extracellular matrix remodeling in the heart and other organs. Activation of the mineralocorticoid receptor (MR) by aldosterone leads to changes in collagen and proteoglycan expression, induces MMP (matrix metalloproteinase) activity, upregulates the expression of profibrotic and proinflammatory cytokines, promotes endothelial-to-mesenchymal transition, and increases oxidative stress. MR effects on extracellular matrix remodeling have been reported in the heart and vasculature, and various other organs, including lung, kidney, liver, and skin. The present study by Ibarrola et al demonstrates that the aldosterone/MR signaling pathway drives mitral valve remodeling.In this issue, Ibarrola et al4 extended this view, demonstrating that the aldosterone/MR signaling pathway drives mitral valve remodeling and suggest MR antagonists as a new therapeutic option to prevent mitral valve prolapse. Mitral regurgitation is a common heart valve disorder. It can occur because of structural deterioration of the mitral valve leaflets or chordal apparatus (primary) or as a result of abnormal ventricular chamber size with advanced heart disease (secondary).5 Primary mitral regurgitation often involves myxomatous degeneration. Disturbance of the extracellular matrix, including proteoglycan deposition, increased activity of matrix metalloproteinases, invasion of immune cells, and inflammatory cytokine release, leads to mitral valve prolapse. Severe mitral regurgitation can progress to heart failure, arrhythmia, and sudden cardiac death.5 Current treatment options are limited to interventional or surgical repair of advanced mitral regurgitation. However, a pharmacological approach, targeting the pathophysiological basis and thus preventing disease progression, is lacking.5The authors report here the results of a multilevel analysis, providing insight into the relevant cell type(s) and effector molecules of MR in mitral valve remodeling. They conducted extensive in vitro studies to show that aldosterone via MR promotes proteoglycan expression in mitral valve interstitial cells and mesenchymal transition of valve endothelial cells (Figure). They identified CT-1 (cardiotrophin-1) and TLR4 (toll-like receptor 4; CD14) as mediators of these effects downstream of MR in isolated valvular cells. In experimental mouse models, MR antagonist treatment or selective MR deletion in endothelial cells likewise reduced mitral valve remodeling induced by nordexfenfluramine. Finally, in a small cohort of patients with mitral valve prolapse, they observed lower expression of mRNA markers in patients receiving an MR antagonist.This study adds on to a series of studies suggesting that extracellular matrix remodeling is a common pathological effect of MR activation in various tissues (Figure). Besides the well-described profibrotic effect of MR in cardiac ventricular tissue,1,3 it has been shown that MR signaling in osteoblasts is involved in atrial fibrosis development.6 In addition, MR is considered as a main driver of perivascular fibrosis in the presence of cardiovascular risk factors.2 Moreover, there is increasing evidence that MR activation controls extracellular matrix composition in extracardiac tissues. MR antagonists prevent the upregulation of profibrotic molecules and interstitial fibrosis in response to kidney injury.3 Hypoxia-induced local production of aldosterone by pulmonary artery endothelial cells promotes pulmonary vascular fibrosis.7 In the skin, MR controls collagen expression in skin fibroblasts.8 MR antagonists have been used as diuretics in liver cirrhosis for a long time, however, recent data suggest a direct beneficial effect of MR antagonists on liver fibrosis and disease progression (Figure).9The findings from this study contribute to our expanding knowledge on the common and distinct effects of MR in different cardiovascular cell types.1,2 The authors used the Cre/loxP system under control of the cadherin 5 or the alpha-SMA (alpha-smooth muscle actin) promoter to delete MR in valve endothelial cells or interstitial cells, respectively. The beneficial effect of MR deletion in endothelial cells on mitral valve remodeling is in line with the previous finding that MR in vascular endothelial cells drives cardiac inflammation and fibrosis, inhibits angiogenesis, and impairs left ventricular function.10–12 Given the comparably low expression of MR in valve endothelial cells versus interstitial cells, it is remarkable that cadherin 5- but not alpha-SMA-driven MR deletion influenced mitral valve remodeling. However, alpha-SMA is considered to be a marker of activated valve interstitial cells. Thus, it is plausible that low expression of alpha-SMA in quiescent valve interstitial cells may have prevented efficient Cre-mediated recombination, which is an important limitation to the study.The centrality of heterocellular interactions in mitral valve remodeling is highlighted by the observed paracrine effects of CT-1 and CD14 on valve endothelial cells or interstitial cells, respectively. The present findings expand earlier studies by Dr López-Andrés on the profibrotic effect of CT-1, a member of the IL-6 cytokine family. For example, they could recently show that CT-1 induced cardiac fibroblast activity and myocardial fibrosis via upregulation of the proinflammatory and profibrotic molecule galectin 3.13 It would be of great interest to see whether these paracrine mechanisms involve other cell types and how they affect mitral valve disease. For example, it has been shown that altered extracellular matrix composition and cytokine expression induce secondary accumulation and activation of macrophages, further promoting mitral valve remodeling.14 Previous studies have convincingly demonstrated that MR in macrophages drives macrophage M1 activation, increases the expression of inflammatory and profibrotic cytokines, and leads to macrophage accumulation in the heart and perivascular tissue.1 However, CT-1 may also have anti-inflammatory effects on macrophages, thus potentially counteracting the effects of aldosterone. Therefore, the role of macrophage MR in mitral valve remodeling remains to be explored.Given the high prevalence of mitral valve prolapse and the clinical availability of MR antagonists, the findings presented in this study have important translational potential. However, the ideal candidate patient collective has to be defined. In earlier studies, MR antagonist treatment improved the outcome of dogs with moderate to severe mitral regurgitation because of myxomatous mitral valve disease.15 It remained unclear whether this was related to improved mitral valve remodeling or heart failure. In the present study, MR antagonist treatment had only modest effects on mRNA marker expression and extracellular matrix composition in patients with severe mitral valve regurgitation and mild to moderate symptoms. In contrast, when administered in a preventive approach together with nordexfenfluramine in mice, spironolactone markedly improved mitral valve remodeling. This suggests that future clinical studies should explore the functional impact of MR antagonists on the progression of early stage mitral regurgitation and prolapse.In summary, Ibarolla et al demonstrate that the aldosterone/MR signaling pathway drives mitral valve remodeling and suggest MR antagonists as a new therapeutic option to prevent mitral valve prolapse. This study extends our knowledge on the cell type-specific role of MR as a master regulator of extracellular matrix remodeling in the heart and in various other tissues.Sources of FundingA. Lother is a member of CRC1425, funded by the German Research Foundation, and funded by the Berta-Ottenstein-Programme for Advanced Clinician Scientists, Faculty of Medicine, University of Freiburg.DisclosuresNone.FootnotesFor Sources of Funding and Disclosures, see page 356.Correspondence to: Achim Lother, Department of Cardiology and Angiology I, Heart Center Freiburg University, Hugstetter Str. 55, 79106 Freiburg, Germany. Email achim.[email protected]rzzentrum.deReferences1. Lother A, Moser M, Bode C, Feldman RD, Hein L. Mineralocorticoids in the heart and vasculature: new insights for old hormones.Annu Rev Pharmacol Toxicol. 2015; 55:289–312. doi: 10.1146/annurev-pharmtox-010814-124302CrossrefMedlineGoogle Scholar2. Lother A, Hein L. Vascular mineralocorticoid receptors: linking risk factors, hypertension, and heart disease.Hypertension. 2016; 68:6–10. doi: 10.1161/HYPERTENSIONAHA.116.07418LinkGoogle Scholar3. Bauersachs J, Jaisser F, Toto R. Mineralocorticoid receptor activation and mineralocorticoid receptor antagonist treatment in cardiac and renal diseases.Hypertension. 2015; 65:257–263. doi: 10.1161/HYPERTENSIONAHA.114.04488LinkGoogle Scholar4. Ibarrola J, Garcia-Peña A, Matilla L, Bonnard B, Sádaba R, Arrieta V, Alvarez V, Fernández-Celis A, Gainza A, Navarro A, et al. A new role for the aldosterone/mineralocorticoid receptor pathway in the development of mitral valve prolapse.Circ Res. 2020; 127:e80–e93. doi: 10.1161/CIRCRESAHA.119.316427LinkGoogle Scholar5. Nishimura RA, Vahanian A, Eleid MF, Mack MJ. Mitral valve disease–current management and future challenges.Lancet. 2016; 387:1324–1334. doi: 10.1016/S0140-6736(16)00558-4CrossrefMedlineGoogle Scholar6. Yi Y, Du L, Qin M, Chen XQ, Sun XN, Li C, Du LJ, Liu Y, Liu Y, Sun JY, et al. Regulation of atrial fibrosis by the bone.Hypertension. 2019; 73:379–389. doi: 10.1161/HYPERTENSIONAHA.118.11544LinkGoogle Scholar7. Maron BA, Oldham WM, Chan SY, Vargas SO, Arons E, Zhang YY, Loscalzo J, Leopold JA. Upregulation of steroidogenic acute regulatory protein by hypoxia stimulates aldosterone synthesis in pulmonary artery endothelial cells to promote pulmonary vascular fibrosis.Circulation. 2014; 130:168–179. doi: 10.1161/CIRCULATIONAHA.113.007690LinkGoogle Scholar8. Boix J, Nguyen VT, Farman N, Aractingi S, Pérez P. Mineralocorticoid receptor blockade improves glucocorticoid-induced skin atrophy but partially ameliorates anti-inflammatory actions in an irritative model in human skin explants.Exp Dermatol. 2018; 27:185–187. doi: 10.1111/exd.13473CrossrefMedlineGoogle Scholar9. Schreier B, Wolf A, Hammer S, Pohl S, Mildenberger S, Rabe S, Gekle M, Zipprich A. The selective mineralocorticoid receptor antagonist eplerenone prevents decompensation of the liver in cirrhosis.Br J Pharmacol. 2018; 175:2956–2967. doi: 10.1111/bph.14341CrossrefMedlineGoogle Scholar10. Lother A, Deng L, Huck M, Fürst D, Kowalski J, Esser JS, Moser M, Bode C, Hein L. Endothelial cell mineralocorticoid receptors oppose VEGF-induced gene expression and angiogenesis.J Endocrinol. 2019; 240:15–26. doi: 10.1530/JOE-18-0494CrossrefMedlineGoogle Scholar11. Lother A, Fürst D, Bergemann S, Gilsbach R, Grahammer F, Huber TB, Hilgendorf I, Bode C, Moser M, Hein L. Deoxycorticosterone acetate/salt-induced cardiac but not renal injury is mediated by endothelial mineralocorticoid receptors independently from blood pressure.Hypertension. 2016; 67:130–138. doi: 10.1161/HYPERTENSIONAHA.115.06530LinkGoogle Scholar12. Jia G, Habibi J, DeMarco VG, Martinez-Lemus LA, Ma L, Whaley-Connell AT, Aroor AR, Domeier TL, Zhu Y, Meininger GA, et al. Endothelial mineralocorticoid receptor deletion prevents diet-induced cardiac diastolic dysfunction in females.Hypertension. 2015; 66:1159–1167. doi: 10.1161/HYPERTENSIONAHA.115.06015LinkGoogle Scholar13. Martínez-Martínez E, Brugnolaro C, Ibarrola J, Ravassa S, Buonafine M, López B, Fernández-Celis A, Querejeta R, Santamaria E, Fernández-Irigoyen J, et al. CT-1 (cardiotrophin-1)-gal-3 (galectin-3) axis in cardiac fibrosis and inflammation.Hypertension. 2019; 73:602–611. doi: 10.1161/HYPERTENSIONAHA.118.11874LinkGoogle Scholar14. Kim AJ, Xu N, Yutzey KE. Macrophage lineages in heart valve development and disease.Cardiovasc Res. 2020:cvaa062. doi: 10.1093/cvr/cvaa062CrossrefMedlineGoogle Scholar15. Bernay F, Bland JM, Häggström J, Baduel L, Combes B, Lopez A, Kaltsatos V. Efficacy of spironolactone on survival in dogs with naturally occurring mitral regurgitation caused by myxomatous mitral valve disease.J Vet Intern Med. 2010; 24:331–341. doi: 10.1111/j.1939-1676.2009.0467.xCrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Mamazhakypov A, Hein L and Lother A (2022) Mineralocorticoid receptors in pulmonary hypertension and right heart failure: From molecular biology to therapeutic targeting, Pharmacology & Therapeutics, 10.1016/j.pharmthera.2021.107987, 231, (107987), Online publication date: 1-Mar-2022. Cai M, McNamara K, Yamazaki Y, Harada N, Miyashita M, Tada H, Ishida T and Sasano H (2022) The role of mineralocorticoids and glucocorticoids under the impact of 11β-hydroxysteroid dehydrogenase in human breast lesions, Medical Molecular Morphology, 10.1007/s00795-022-00312-1, 55:2, (110-122), Online publication date: 1-Jun-2022. Bauersachs J and Lother A (2022) Mineralocorticoid receptor activation and antagonism in cardiovascular disease: cellular and molecular mechanisms, Kidney International Supplements, 10.1016/j.kisu.2021.11.001, 12:1, (19-26), Online publication date: 1-Apr-2022. Kotfis K, Lechowicz K, Drożdżal S, Niedźwiedzka-Rystwej P, Wojdacz T, Grywalska E, Biernawska J, Wiśniewska M and Parczewski M (2021) COVID-19—The Potential Beneficial Therapeutic Effects of Spironolactone during SARS-CoV-2 Infection, Pharmaceuticals, 10.3390/ph14010071, 14:1, (71) Related articlesA New Role for the Aldosterone/Mineralocorticoid Receptor Pathway in the Development of Mitral Valve ProlapseJaime Ibarrola, et al. Circulation Research. 2020;127:e80-e93 July 17, 2020Vol 127, Issue 3 Advertisement Article InformationMetrics © 2020 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.120.317424PMID: 32673533 Originally publishedJuly 16, 2020 PDF download Advertisement
Referência(s)