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Gu H, Chen Z, Du N, Yang S, Yu Y, Du Y. The Effects of Aldosterone on Hypertension-Associated Kidney Injury in a Tg-hAS Mouse Model. BIOLOGY 2024; 13:1084. [PMID: 39765751 PMCID: PMC11673120 DOI: 10.3390/biology13121084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 12/08/2024] [Accepted: 12/20/2024] [Indexed: 01/11/2025]
Abstract
Hypertension remains a global health challenge due to its high prevalence and association with premature morbidity and mortality. Aldosterone, a mineralocorticoid hormone, and its receptor, the mineralocorticoid receptor (MR), are highly implicated in hypertension pathogenesis. Aldosterone synthase is the sole enzyme responsible for producing aldosterone in humans. We established transgenic mice carrying the human aldosterone synthase gene (cyp11B2) and showed dramatically increased levels of aldosterone in female hemizygotes. High-salt diets persistently increased blood pressure in these mice, and salt-induced hypertension was significantly ameliorated by reducing aldosterone levels via an aldosterone synthase inhibitor or blocking MR via an MR inhibitor. Since both hypertension and hyperaldosteronism specifically induce chronic kidney disease, in this model, we demonstrated that chronic high-salt diets induced hypertension in this mouse line and resulted in kidney inflammation and injury. Both the aldosterone synthase inhibitor and the MR antagonist markedly blocked high-salt-diet-mediated kidney injury. Thus, this transgenic mouse line can be used to study the pathogenic mechanisms underlying aldosterone and its receptor and to screen therapeutic compounds for aldosterone-mediated hypertension and related complications, such as kidney disease, in humans.
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Affiliation(s)
- Huiying Gu
- Department of Neurology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (H.G.); (Z.C.); (S.Y.); (Y.Y.)
| | - Zhe Chen
- Department of Neurology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (H.G.); (Z.C.); (S.Y.); (Y.Y.)
| | - Nicole Du
- Boston Children’s Hospital, Boston, MA 02115, USA;
| | - Sisi Yang
- Department of Neurology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (H.G.); (Z.C.); (S.Y.); (Y.Y.)
| | - Yongqi Yu
- Department of Neurology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (H.G.); (Z.C.); (S.Y.); (Y.Y.)
| | - Yansheng Du
- Department of Neurology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (H.G.); (Z.C.); (S.Y.); (Y.Y.)
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2
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Ho QV, Young MJ. Mineralocorticoid receptors, macrophages and new mechanisms for cardiovascular disease. Mol Cell Endocrinol 2024; 593:112340. [PMID: 39134137 DOI: 10.1016/j.mce.2024.112340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2024] [Revised: 08/01/2024] [Accepted: 08/05/2024] [Indexed: 08/16/2024]
Affiliation(s)
- Quoc Viet Ho
- Cardiovascular Endocrinology Laboratory, Baker Heart and Diabetes Institute, Australia
| | - Morag J Young
- Cardiovascular Endocrinology Laboratory, Baker Heart and Diabetes Institute, Australia; Department of Cardiometabolic Health, University of Melbourne, Victoria, Australia.
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3
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Rendell M. Lessons learned from early-stage clinical trials for diabetic nephropathy. Expert Opin Investig Drugs 2024; 33:287-301. [PMID: 38465470 DOI: 10.1080/13543784.2024.2326025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Accepted: 02/28/2024] [Indexed: 03/12/2024]
Abstract
INTRODUCTION The evolution of treatment for diabetic nephropathy illustrates how basic biochemistry and physiology have led to new agents such as SGLT2 inhibitors and mineralocorticoid blockers. Conversely, clinical studies performed with these agents have suggested new concepts for investigational drug development. We reviewed currently available treatments for diabetic nephropathy and then analyzed early clinical trials of new agents to assess the potential for future treatment modalities. AREAS COVERED We searched ClinicalTrials.gov for new agents under study for diabetic nephropathy in the past decade. Once we have identified investigation trials of new agents, we then used search engines and Pubmed.gov to find publications providing insight on these drugs. Current treatments have shown benefit in both cardiac and renal disease. In our review, we found 51 trials and 43 pharmaceuticals in a number of drug classes: mineralocorticoid blockers, anti-inflammatory, anti-fibrosis, nitric oxide stimulatory, and podocyte protection, and endothelin inhibitors. EXPERT OPINION It is difficult to predict which early phase treatments will advance to confirmatory clinical trials. Current agents are thought to improve hemodynamic function. However, the coincident benefit of both myocardial function and the glomerulus argues for primary effects at the subcellular level, and we follow the evolution of agents which modify fundamental cellular processes.
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Affiliation(s)
- Marc Rendell
- The Association of Diabetes Investigators, Newport Coast, CA, USA
- The Rose Salter Medical Research Foundation, Newport Coast, CA, USA
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4
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Awosika A, Khan A, Adabanya U, Omole AE, Millis RM. Aldosterone Synthase Inhibitors and Dietary Interventions: A Combined Novel Approach for Prevention and Treatment of Cardiovascular Disease. Cureus 2023; 15:e36184. [PMID: 36937127 PMCID: PMC10016316 DOI: 10.7759/cureus.36184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/15/2023] [Indexed: 03/17/2023] Open
Abstract
Systemic hypertension (HTN) is the hallmark of cardiovascular disease and the forerunner of heart failure. These associations have been established over decades of research on essential HTN. Advancements in the treatment of patients diagnosed with HTN, consisting of alpha- or beta-adrenergic receptor blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, thiazide, or aldosterone receptor blockers known as anti-mineralocorticoids, in the presence or absence of low sodium salt diets, often fail to control blood pressure adequately to prevent morbidity and mortality. Low sodium diets have had limited success in controlling HTN because low sodium intake is associated with renin-angiotensin-aldosterone system upregulation. Therefore, upregulating aldosterone secretion, sodium, and water retention which, in turn, moves the blood pressure back toward the range of HTN dictated by the baroreceptor reset value, as a compensatory mechanism, especially in resistant HTN. These impediments to blood pressure control in HTN may have been effectively circumvented by the advent of a new class of drugs known as aldosterone synthase inhibitors, represented by baxdrostat. The mechanism of action of baxdrostat as an aldosterone synthase inhibitor demonstrates the inextricable linkage between sodium and blood pressure regulation. Theoretically, combining a low sodium diet with the activity of this aldosterone synthesis inhibitor should alleviate the adverse effect of renin-angiotensin-aldosterone system upregulation. Aldosterone synthesis inhibition should also decrease the oxidative stress and endothelial dysfunction associated with HTN, causing more endothelial nitric oxide synthesis, release, and vasorelaxation. To the best of our knowledge, this is the first systematic review to summarize evidence-based articles relevant to the use of a novel drug (aldosterone synthase inhibitor) in the treatment of HTN and cardiovascular disease. Making the current database of relevant information on baxdrostat and other aldosterone synthase inhibitors readily available will, no doubt, aid physicians and other medical practitioners in their decision-making about employing aldosterone synthase inhibitors in the treatment of patients.
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Affiliation(s)
- Ayoola Awosika
- College of Medicine, University of Illinois Chicago, Chicago, USA
| | - Anosh Khan
- Internal Medicine, Spartan Health Sciences University School of Medicine, Vieux Fort, LCA
| | | | - Adekunle E Omole
- Anatomical Sciences, American University of Antigua College of Medicine, Coolidge, ATG
| | - Richard M Millis
- Pathophysiology, American University of Antigua College of Medicine, Coolidge, ATG
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5
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Non-genomic uterorelaxant actions of corticosteroid hormones in rats: An in vitro and in vivo study. Eur J Pharmacol 2022; 935:175346. [DOI: 10.1016/j.ejphar.2022.175346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 10/17/2022] [Accepted: 10/18/2022] [Indexed: 11/19/2022]
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Pollard CM, Suster MS, Cora N, Carbone AM, Lymperopoulos A. GRK5 is an essential co-repressor of the cardiac mineralocorticoid receptor and is selectively induced by finerenone. World J Cardiol 2022; 14:220-230. [PMID: 35582468 PMCID: PMC9048278 DOI: 10.4330/wjc.v14.i4.220] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 02/17/2022] [Accepted: 03/27/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND In the heart, aldosterone (Aldo) binds the mineralocorticoid receptor (MR) to exert damaging, adverse remodeling-promoting effects. We recently showed that G protein-coupled receptor-kinase (GRK)-5 blocks the cardiac MR by directly phosphorylating it, thereby repressing its transcriptional activity. MR antagonist (MRA) drugs block the cardiac MR reducing morbidity and mortality of advanced human heart failure. Non-steroidal MRAs, such as finerenone, may provide better cardio-protection against Aldo than classic, steroidal MRAs, like spironolactone and eplerenone. AIM To investigate potential differences between finerenone and eplerenone at engaging GRK5-dependent cardiac MR phosphorylation and subsequent blockade. METHODS We used H9c2 cardiomyocytes, which endogenously express the MR and GRK5. RESULTS GRK5 phosphorylates the MR in H9c2 cardiomyocytes in response to finerenone but not to eplerenone. Unlike eplerenone, finerenone alone potently and efficiently suppresses cardiac MR transcriptional activity, thus displaying inverse agonism. GRK5 is necessary for finerenone's inverse agonism, since GRK5 genetic deletion renders finerenone incapable of blocking cardiac MR transcriptional activity. Eplerenone alone does not fully suppress cardiac MR basal activity regardless of GRK5 expression levels. Finally, GRK5 is necessary for the anti-apoptotic, anti-oxidative, and anti-fibrotic effects of both finerenone and eplerenone against Aldo, as well as for the higher efficacy and potency of finerenone at blocking Aldo-induced apoptosis, oxidative stress, and fibrosis. CONCLUSION Finerenone, but not eplerenone, induces GRK5-dependent cardiac MR inhibition, which underlies, at least in part, its higher potency and efficacy, compared to eplerenone, as an MRA in the heart. GRK5 acts as a co-repressor of the cardiac MR and is essential for efficient MR antagonism in the myocardium.
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Affiliation(s)
- Celina M Pollard
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, United States
| | - Malka S Suster
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, United States
| | - Natalie Cora
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, United States
| | - Alexandra M Carbone
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, United States
| | - Anastasios Lymperopoulos
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, United States.
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Karst H, den Boon FS, Vervoort N, Adrian M, Kapitein LC, Joëls M. Non-genomic steroid signaling through the mineralocorticoid receptor: Involvement of a membrane-associated receptor? Mol Cell Endocrinol 2022; 541:111501. [PMID: 34740745 DOI: 10.1016/j.mce.2021.111501] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 10/05/2021] [Accepted: 10/27/2021] [Indexed: 12/25/2022]
Abstract
Corticosteroid receptors in the mammalian brain mediate genomic as well as non-genomic actions. Although receptors mediating genomic actions were already cloned 35 years ago, it remains unclear whether the same molecules are responsible for the non-genomic actions or that the latter involve a separate class of receptors. Here we focus on one type of corticosteroid receptors, i.e. the mineralocorticoid receptor (MR). We summarize some of the known properties and the current insight in the localization of the MR in peripheral cells and neurons, especially in relation to non-genomic signaling. Previous studies from our own and other labs provided evidence that MRs mediating non-genomic actions are identical to the ones involved in genomic signaling, but may be translocated to the plasma cell membrane instead of the nucleus. With fixed cell imaging and live cell imaging techniques we tried to visualize these presumed membrane-associated MRs, using antibodies or overexpression of MR-GFP in COS7 and hippocampal cultured neurons. Despite the physiological evidence for MR location in or close to the cell membrane, we could not convincingly visualize membrane localization of endogenous MRs or GFP-MR molecules. However, we did find punctae of labeled antibodies intracellularly, which might indicate transactivating spots of MR near the membrane. We also found some evidence for trafficking of MR via beta-arrestins. In beta-arrestin knockout mice, we didn't observe metaplasticity in the basolateral amygdala anymore, indicating that internalization of MRs could play a role during corticosterone activation. Furthermore, we speculate that membrane-associated MRs could act indirectly via activating other membrane located structures like e.g. GPER and/or receptor tyrosine kinases.
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Affiliation(s)
- Henk Karst
- Dept Translational Neuroscience, University Medical Center Utrecht, Utrecht University, the Netherlands.
| | - Femke S den Boon
- Dept Translational Neuroscience, University Medical Center Utrecht, Utrecht University, the Netherlands
| | - Niek Vervoort
- University Utrecht, Faculty of Science, Division of Cell Biology, Utrecht, the Netherlands
| | - Max Adrian
- University Utrecht, Faculty of Science, Division of Cell Biology, Utrecht, the Netherlands
| | - Lukas C Kapitein
- University Utrecht, Faculty of Science, Division of Cell Biology, Utrecht, the Netherlands
| | - Marian Joëls
- Dept Translational Neuroscience, University Medical Center Utrecht, Utrecht University, the Netherlands; University Medical Center Groningen, University of Groningen, the Netherlands
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Grossmann C, Almeida-Prieto B, Nolze A, Alvarez de la Rosa D. Structural and molecular determinants of mineralocorticoid receptor signalling. Br J Pharmacol 2021; 179:3103-3118. [PMID: 34811739 DOI: 10.1111/bph.15746] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 10/19/2021] [Accepted: 11/08/2021] [Indexed: 12/18/2022] Open
Abstract
During the past decades, the mineralocorticoid receptor (MR) has evolved from a much-overlooked member of the steroid hormone receptor family to an important player, not only in volume and electrolyte homeostasis but also in pathological changes occurring in an increasing number of tissues, especially the renal and cardiovascular systems. Simultaneously, a wealth of information about the structure, interaction partners and chromatin requirements for genomic signalling of steroid hormone receptors became available. However, much of the information for the MR has been deduced from studies of other family members and there is still a lack of knowledge about MR-specific features in ligand binding, chromatin remodelling, co-factor interactions and general MR specificity-conferring mechanisms that can completely explain the differences in pathophysiological function between MR and its closest relative, the glucocorticoid receptor. This review aims to give an overview of the current knowledge of MR structure, signalling and co-factors modulating its activity.
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Affiliation(s)
- Claudia Grossmann
- Julius Bernstein Institute of Physiology, Martin Luther University Halle-Wittenberg, Halle, Saale, Germany
| | - Brian Almeida-Prieto
- Departamento de Ciencias Médicas Básicas and Instituto de Tecnologías Biomédicas, Universidad de La Laguna, La Laguna, Tenerife, Spain
| | - Alexander Nolze
- Julius Bernstein Institute of Physiology, Martin Luther University Halle-Wittenberg, Halle, Saale, Germany
| | - Diego Alvarez de la Rosa
- Departamento de Ciencias Médicas Básicas and Instituto de Tecnologías Biomédicas, Universidad de La Laguna, La Laguna, Tenerife, Spain
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Yang J, Chen Y, Li X, Xu D. New insights into the roles of glucocorticoid signaling dysregulation in pathological cardiac hypertrophy. Heart Fail Rev 2021; 27:1431-1441. [PMID: 34455516 DOI: 10.1007/s10741-021-10158-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/09/2021] [Indexed: 01/02/2023]
Abstract
Pathological cardiac hypertrophy is a process of abnormal remodeling of the myocardium in response to stress overload or ischemia that results in myocardial injury, which is an independent risk factor for the increased morbidity and mortality of heart failure. Elevated circulating glucocorticoids (GCs) levels are associated with an increased risk of pathological cardiac hypertrophy, but the exact role remains unclear. In the heart, GCs exerts physiological and pharmacological effects by binding the glucocorticoid receptor (GR, NR3C1). However, under the state of tissue damage or oxidative stress, GCs can also bind the closely related mineralocorticoid receptor (MR, NR3C2) to exert a detrimental effect on cardiac function. In addition, the bioavailability of GCs at the cellular level is mainly regulated by tissue-specific metabolic enzymes 11β-hydroxysteroid dehydrogenases (11β-HSDs), including 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and type 2 (11β-HSD2), which catalyze the interconversion of active GCs. In this paper, we provide an overview of GC signaling and its physiological roles in the heart and highlight the dynamic and diverse roles of GC signaling dysregulation, mediated by excessive ligand GCs levels, GR/MR deficiency or overexpression, and local GCs metabolic disorder by 11β-HSDs, in the pathology of cardiac hypertrophy. Our findings will provide new ideas and insights for the search for appropriate intervention targets for pathological cardiac hypertrophy.
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Affiliation(s)
- Jingmin Yang
- Department of Cardiology, The Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, 410000, Hunan, China
| | - Yanying Chen
- Department of Cardiology, The Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, 410000, Hunan, China
| | - Xiao Li
- Department of Cardiology, The Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, 410000, Hunan, China
| | - Danyan Xu
- Department of Cardiology, The Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, 410000, Hunan, China.
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Galigniana MD. Molecular Pharmacology of the Youngest Member of the Nuclear Receptor Family: The Mineralocorticoid Receptor. NUCLEAR RECEPTORS 2021:1-21. [DOI: 10.1007/978-3-030-78315-0_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
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Maning J, McCrink KA, Pollard CM, Desimine VL, Ghandour J, Perez A, Cora N, Ferraino KE, Parker BM, Brill AR, Aukszi B, Lymperopoulos A. Antagonistic Roles of GRK2 and GRK5 in Cardiac Aldosterone Signaling Reveal GRK5-Mediated Cardioprotection via Mineralocorticoid Receptor Inhibition. Int J Mol Sci 2020; 21:2868. [PMID: 32326036 PMCID: PMC7215681 DOI: 10.3390/ijms21082868] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 04/14/2020] [Accepted: 04/17/2020] [Indexed: 12/13/2022] Open
Abstract
Aldosterone (Aldo), when overproduced, is a cardiotoxic hormone underlying heart failure and hypertension. Aldo exerts damaging effects via the mineralocorticoid receptor (MR) but also activates the antiapoptotic G protein-coupled estrogen receptor (GPER) in the heart. G protein-coupled receptor (GPCR)-kinase (GRK)-2 and -5 are the most abundant cardiac GRKs and phosphorylate GPCRs as well as non-GPCR substrates. Herein, we investigated whether they phosphorylate and regulate cardiac MR and GPER. To this end, we used the cardiomyocyte cell line H9c2 and adult rat ventricular myocytes (ARVMs), in which we manipulated GRK5 protein levels via clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 and GRK2 activity via pharmacological inhibition. We report that GRK5 phosphorylates and inhibits the cardiac MR whereas GRK2 phosphorylates and desensitizes GPER. In H9c2 cardiomyocytes, GRK5 interacts with and phosphorylates the MR upon β2-adrenergic receptor (AR) activation. In contrast, GRK2 opposes agonist-activated GPER signaling. Importantly, GRK5-dependent MR phosphorylation of the MR inhibits transcriptional activity, since aldosterone-induced gene transcription is markedly suppressed in GRK5-overexpressing cardiomyocytes. Conversely, GRK5 gene deletion augments cardiac MR transcriptional activity. β2AR-stimulated GRK5 phosphorylates and inhibits the MR also in ARVMs. Additionally, GRK5 is necessary for the protective effects of the MR antagonist drug eplerenone against Aldo-induced apoptosis and oxidative stress in ARVMs. In conclusion, GRK5 blocks the cardiotoxic MR-dependent effects of Aldo in the heart, whereas GRK2 may hinder beneficial effects of Aldo through GPER. Thus, cardiac GRK5 stimulation (e.g., via β2AR activation) might be of therapeutic value for heart disease treatment via boosting the efficacy of MR antagonists against Aldo-mediated cardiac injury.
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Affiliation(s)
- Jennifer Maning
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (J.M.); (K.A.M.); (C.M.P.); (V.L.D.); (J.G.); (A.P.); (N.C.); (K.E.F.); (B.M.P.); (A.R.B.)
| | - Katie A. McCrink
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (J.M.); (K.A.M.); (C.M.P.); (V.L.D.); (J.G.); (A.P.); (N.C.); (K.E.F.); (B.M.P.); (A.R.B.)
| | - Celina M. Pollard
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (J.M.); (K.A.M.); (C.M.P.); (V.L.D.); (J.G.); (A.P.); (N.C.); (K.E.F.); (B.M.P.); (A.R.B.)
| | - Victoria L. Desimine
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (J.M.); (K.A.M.); (C.M.P.); (V.L.D.); (J.G.); (A.P.); (N.C.); (K.E.F.); (B.M.P.); (A.R.B.)
| | - Jennifer Ghandour
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (J.M.); (K.A.M.); (C.M.P.); (V.L.D.); (J.G.); (A.P.); (N.C.); (K.E.F.); (B.M.P.); (A.R.B.)
| | - Arianna Perez
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (J.M.); (K.A.M.); (C.M.P.); (V.L.D.); (J.G.); (A.P.); (N.C.); (K.E.F.); (B.M.P.); (A.R.B.)
| | - Natalie Cora
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (J.M.); (K.A.M.); (C.M.P.); (V.L.D.); (J.G.); (A.P.); (N.C.); (K.E.F.); (B.M.P.); (A.R.B.)
| | - Krysten E. Ferraino
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (J.M.); (K.A.M.); (C.M.P.); (V.L.D.); (J.G.); (A.P.); (N.C.); (K.E.F.); (B.M.P.); (A.R.B.)
| | - Barbara M. Parker
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (J.M.); (K.A.M.); (C.M.P.); (V.L.D.); (J.G.); (A.P.); (N.C.); (K.E.F.); (B.M.P.); (A.R.B.)
| | - Ava R. Brill
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (J.M.); (K.A.M.); (C.M.P.); (V.L.D.); (J.G.); (A.P.); (N.C.); (K.E.F.); (B.M.P.); (A.R.B.)
| | - Beatrix Aukszi
- Department of Chemistry and Physics, Halmos College of Natural Sciences and Oceanography, Nova Southeastern University, Fort Lauderdale, FL 33328, USA;
| | - Anastasios Lymperopoulos
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; (J.M.); (K.A.M.); (C.M.P.); (V.L.D.); (J.G.); (A.P.); (N.C.); (K.E.F.); (B.M.P.); (A.R.B.)
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12
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Schulz A, Richter S, Ferreira de Sá DS, Vögele C, Schächinger H. Cortisol rapidly increases baroreflex sensitivity of heart rate control, but does not affect cardiac modulation of startle. Physiol Behav 2020; 215:112792. [PMID: 31870942 DOI: 10.1016/j.physbeh.2019.112792] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 11/14/2019] [Accepted: 12/19/2019] [Indexed: 11/25/2022]
Abstract
Cortisol, the final product of human HPA axis activation, rapidly modulates the cortical processing of afferent signals originating from the cardiovascular system. While peripheral effects have been excluded, it remains unclear whether this effect is mediated by cortical or subcortical (e.g. brainstem) CNS mechanisms. Cardiac modulation of startle (CMS) has been proposed as a method to reflect cardio-afferent signals at subcortical (potentially brainstem-) level. Using a single blind, randomized controlled design, the cortisol group (n = 16 volunteers) received 1 mg cortisol intravenously, while the control group (n = 16) received a placebo substance. The CMS procedure involved the assessment of eye blink responses to acoustic startle stimuli elicited at six different latencies to ECG-recorded R-waves (R + 0, 100, 200, 300, 400 and 500 ms). CMS was assessed at four measurement points: baseline, -16 min, +0 min, and +16 min relative to substance application. Baroreflex sensitivity (BRS) of heart rate (HR) control was measured non-invasively based on spontaneous beat-to-beat HR and systolic blood pressure changes. In the cortisol group, salivary cortisol concentration increased after IV cortisol administration, indicating effective distribution of the substance throughout the body. Furthermore, BRS increased in the cortisol group after cortisol infusion. There was no effect of cortisol on the CMS effect, however. These results suggest that low doses of cortisol do not affect baro-afferent signals, but central or efferent components of the arterial baroreflex circuit presumably via rapid, non-genomic mechanisms.
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Affiliation(s)
- André Schulz
- Institute for Health and Behaviour, Department of Behavioural and Cognitive Sciences, Faculty of Humanities, Education and Social Sciences, University of Luxembourg, 11, Porte des Sciences, Esch-sur-Alzette L-4366, Luxembourg; Division of Clinical Psychophysiology, Institute of Psychobiology, University of Trier, Trier, Germany.
| | - Steffen Richter
- Division of Clinical Psychophysiology, Institute of Psychobiology, University of Trier, Trier, Germany; Competence Center of Sleep Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Diana S Ferreira de Sá
- Division of Clinical Psychophysiology, Institute of Psychobiology, University of Trier, Trier, Germany; Division of Clinical Psychology and Psychotherapy, Department of Psychology, Saarland University, Saarbrücken, Germany
| | - Claus Vögele
- Institute for Health and Behaviour, Department of Behavioural and Cognitive Sciences, Faculty of Humanities, Education and Social Sciences, University of Luxembourg, 11, Porte des Sciences, Esch-sur-Alzette L-4366, Luxembourg
| | - Hartmut Schächinger
- Division of Clinical Psychophysiology, Institute of Psychobiology, University of Trier, Trier, Germany
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Fuller PJ, Yang J, Young MJ. Mechanisms of Mineralocorticoid Receptor Signaling. VITAMINS AND HORMONES 2019; 109:37-68. [DOI: 10.1016/bs.vh.2018.09.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Young MJ, Adler GK. Aldosterone, the Mineralocorticoid Receptor and Mechanisms of Cardiovascular Disease. VITAMINS AND HORMONES 2019; 109:361-385. [DOI: 10.1016/bs.vh.2018.10.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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Abstract
Aldosterone is a mineralocorticoid hormone, as its main renal effect has been considered as electrolyte and water homeostasis in the distal tubule, thus maintaining blood pressure and extracellular fluid homeostasis through the activation of mineralocorticoid receptor (MR) in epithelial cells. However, over the past decade, numerous studies have documented the significant role of aldosterone in the progression of chronic kidney disease (CKD) which has become a subject of interest. It is being studied that aldosterone can affect cardiovascular and renal system, thereby contributing to tissue inflammation, injury, glomerulosclerosis, and interstitial fibrosis. Aldosterone acts on renal vessels, renal cells (glomerular mesangial cells, podocytes, vascular smooth muscle cells, tubular epithelial cells, and interstitial fibroblasts), and infiltrating inflammatory cells, inducing reactive oxygen species (ROS) production, upregulated epithelial growth factor receptor (EGFR), and type 1 angiotensin (AT1) receptor expressions, and activating nuclear factor kappa B (NF-κB), activator protein-1 (AP-1), and EGFR to further promote cell proliferation, apoptosis, and proliferation. Phenotypic transformation of epithelial cells stimulates the expression of transforming growth factor-β (TGF-β), connective tissue growth factor (CTGF), osteopontin (OPN), and plasminogen activator inhibitor-1 (PAI-1), eventually leading to renal fibrosis. MR antagonisms are related to inhibition of aldosterone-mediated pro-inflammatory and pro-fibrotic effect. In this review, we will summarize the important role of aldosterone in the pathogenesis of renal injury and fibrosis, emphasizing on its multiple underlying mechanisms and advances in aldosterone research along with the potential therapeutics for targeting MR in a renal fibrosis.
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Mesquita TR, Auguste G, Falcón D, Ruiz-Hurtado G, Salazar-Enciso R, Sabourin J, Lefebvre F, Viengchareun S, Kobeissy H, Lechène P, Nicolas V, Fernandez-Celis A, Gómez S, Lauton Santos S, Morel E, Rueda A, López-Andrés N, Gómez AM, Lombès M, Benitah JP. Specific Activation of the Alternative Cardiac Promoter of
Cacna1c
by the Mineralocorticoid Receptor. Circ Res 2018; 122:e49-e61. [DOI: 10.1161/circresaha.117.312451] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2017] [Revised: 02/15/2018] [Accepted: 02/19/2018] [Indexed: 11/16/2022]
Affiliation(s)
- Thassio R. Mesquita
- From the Signalisation et Physiopathologie Cardiovasculaire - UMR-S 1180, (T.R.M., G.A., D.F., G.R.-H., J.S., F.L., P.L., S.G., E.M., A.M.G., J.-P.B.), EA 4043 UBaPS (H.K.), and UMS-IPSIT, MIPSIT_Microscopy Facility (V.N.), Univ. Paris-Sud, INSERM, Université Paris-Saclay, 92296, Châtenay-Malabry, France; Department of Physiology, Federal University of Sergipe, Brazil (T.R.M., S.L.S.); Departamento de Bioquímica, Centro de Investigación y de Estudios Avanzados del IPN, México City, D.F., México (R.S
| | - Gaëlle Auguste
- From the Signalisation et Physiopathologie Cardiovasculaire - UMR-S 1180, (T.R.M., G.A., D.F., G.R.-H., J.S., F.L., P.L., S.G., E.M., A.M.G., J.-P.B.), EA 4043 UBaPS (H.K.), and UMS-IPSIT, MIPSIT_Microscopy Facility (V.N.), Univ. Paris-Sud, INSERM, Université Paris-Saclay, 92296, Châtenay-Malabry, France; Department of Physiology, Federal University of Sergipe, Brazil (T.R.M., S.L.S.); Departamento de Bioquímica, Centro de Investigación y de Estudios Avanzados del IPN, México City, D.F., México (R.S
| | - Débora Falcón
- From the Signalisation et Physiopathologie Cardiovasculaire - UMR-S 1180, (T.R.M., G.A., D.F., G.R.-H., J.S., F.L., P.L., S.G., E.M., A.M.G., J.-P.B.), EA 4043 UBaPS (H.K.), and UMS-IPSIT, MIPSIT_Microscopy Facility (V.N.), Univ. Paris-Sud, INSERM, Université Paris-Saclay, 92296, Châtenay-Malabry, France; Department of Physiology, Federal University of Sergipe, Brazil (T.R.M., S.L.S.); Departamento de Bioquímica, Centro de Investigación y de Estudios Avanzados del IPN, México City, D.F., México (R.S
| | - Gema Ruiz-Hurtado
- From the Signalisation et Physiopathologie Cardiovasculaire - UMR-S 1180, (T.R.M., G.A., D.F., G.R.-H., J.S., F.L., P.L., S.G., E.M., A.M.G., J.-P.B.), EA 4043 UBaPS (H.K.), and UMS-IPSIT, MIPSIT_Microscopy Facility (V.N.), Univ. Paris-Sud, INSERM, Université Paris-Saclay, 92296, Châtenay-Malabry, France; Department of Physiology, Federal University of Sergipe, Brazil (T.R.M., S.L.S.); Departamento de Bioquímica, Centro de Investigación y de Estudios Avanzados del IPN, México City, D.F., México (R.S
| | - Rogelio Salazar-Enciso
- From the Signalisation et Physiopathologie Cardiovasculaire - UMR-S 1180, (T.R.M., G.A., D.F., G.R.-H., J.S., F.L., P.L., S.G., E.M., A.M.G., J.-P.B.), EA 4043 UBaPS (H.K.), and UMS-IPSIT, MIPSIT_Microscopy Facility (V.N.), Univ. Paris-Sud, INSERM, Université Paris-Saclay, 92296, Châtenay-Malabry, France; Department of Physiology, Federal University of Sergipe, Brazil (T.R.M., S.L.S.); Departamento de Bioquímica, Centro de Investigación y de Estudios Avanzados del IPN, México City, D.F., México (R.S
| | - Jessica Sabourin
- From the Signalisation et Physiopathologie Cardiovasculaire - UMR-S 1180, (T.R.M., G.A., D.F., G.R.-H., J.S., F.L., P.L., S.G., E.M., A.M.G., J.-P.B.), EA 4043 UBaPS (H.K.), and UMS-IPSIT, MIPSIT_Microscopy Facility (V.N.), Univ. Paris-Sud, INSERM, Université Paris-Saclay, 92296, Châtenay-Malabry, France; Department of Physiology, Federal University of Sergipe, Brazil (T.R.M., S.L.S.); Departamento de Bioquímica, Centro de Investigación y de Estudios Avanzados del IPN, México City, D.F., México (R.S
| | - Florence Lefebvre
- From the Signalisation et Physiopathologie Cardiovasculaire - UMR-S 1180, (T.R.M., G.A., D.F., G.R.-H., J.S., F.L., P.L., S.G., E.M., A.M.G., J.-P.B.), EA 4043 UBaPS (H.K.), and UMS-IPSIT, MIPSIT_Microscopy Facility (V.N.), Univ. Paris-Sud, INSERM, Université Paris-Saclay, 92296, Châtenay-Malabry, France; Department of Physiology, Federal University of Sergipe, Brazil (T.R.M., S.L.S.); Departamento de Bioquímica, Centro de Investigación y de Estudios Avanzados del IPN, México City, D.F., México (R.S
| | - Say Viengchareun
- From the Signalisation et Physiopathologie Cardiovasculaire - UMR-S 1180, (T.R.M., G.A., D.F., G.R.-H., J.S., F.L., P.L., S.G., E.M., A.M.G., J.-P.B.), EA 4043 UBaPS (H.K.), and UMS-IPSIT, MIPSIT_Microscopy Facility (V.N.), Univ. Paris-Sud, INSERM, Université Paris-Saclay, 92296, Châtenay-Malabry, France; Department of Physiology, Federal University of Sergipe, Brazil (T.R.M., S.L.S.); Departamento de Bioquímica, Centro de Investigación y de Estudios Avanzados del IPN, México City, D.F., México (R.S
| | - Hussein Kobeissy
- From the Signalisation et Physiopathologie Cardiovasculaire - UMR-S 1180, (T.R.M., G.A., D.F., G.R.-H., J.S., F.L., P.L., S.G., E.M., A.M.G., J.-P.B.), EA 4043 UBaPS (H.K.), and UMS-IPSIT, MIPSIT_Microscopy Facility (V.N.), Univ. Paris-Sud, INSERM, Université Paris-Saclay, 92296, Châtenay-Malabry, France; Department of Physiology, Federal University of Sergipe, Brazil (T.R.M., S.L.S.); Departamento de Bioquímica, Centro de Investigación y de Estudios Avanzados del IPN, México City, D.F., México (R.S
| | - Patrick Lechène
- From the Signalisation et Physiopathologie Cardiovasculaire - UMR-S 1180, (T.R.M., G.A., D.F., G.R.-H., J.S., F.L., P.L., S.G., E.M., A.M.G., J.-P.B.), EA 4043 UBaPS (H.K.), and UMS-IPSIT, MIPSIT_Microscopy Facility (V.N.), Univ. Paris-Sud, INSERM, Université Paris-Saclay, 92296, Châtenay-Malabry, France; Department of Physiology, Federal University of Sergipe, Brazil (T.R.M., S.L.S.); Departamento de Bioquímica, Centro de Investigación y de Estudios Avanzados del IPN, México City, D.F., México (R.S
| | - Valérie Nicolas
- From the Signalisation et Physiopathologie Cardiovasculaire - UMR-S 1180, (T.R.M., G.A., D.F., G.R.-H., J.S., F.L., P.L., S.G., E.M., A.M.G., J.-P.B.), EA 4043 UBaPS (H.K.), and UMS-IPSIT, MIPSIT_Microscopy Facility (V.N.), Univ. Paris-Sud, INSERM, Université Paris-Saclay, 92296, Châtenay-Malabry, France; Department of Physiology, Federal University of Sergipe, Brazil (T.R.M., S.L.S.); Departamento de Bioquímica, Centro de Investigación y de Estudios Avanzados del IPN, México City, D.F., México (R.S
| | - Amaya Fernandez-Celis
- From the Signalisation et Physiopathologie Cardiovasculaire - UMR-S 1180, (T.R.M., G.A., D.F., G.R.-H., J.S., F.L., P.L., S.G., E.M., A.M.G., J.-P.B.), EA 4043 UBaPS (H.K.), and UMS-IPSIT, MIPSIT_Microscopy Facility (V.N.), Univ. Paris-Sud, INSERM, Université Paris-Saclay, 92296, Châtenay-Malabry, France; Department of Physiology, Federal University of Sergipe, Brazil (T.R.M., S.L.S.); Departamento de Bioquímica, Centro de Investigación y de Estudios Avanzados del IPN, México City, D.F., México (R.S
| | - Susana Gómez
- From the Signalisation et Physiopathologie Cardiovasculaire - UMR-S 1180, (T.R.M., G.A., D.F., G.R.-H., J.S., F.L., P.L., S.G., E.M., A.M.G., J.-P.B.), EA 4043 UBaPS (H.K.), and UMS-IPSIT, MIPSIT_Microscopy Facility (V.N.), Univ. Paris-Sud, INSERM, Université Paris-Saclay, 92296, Châtenay-Malabry, France; Department of Physiology, Federal University of Sergipe, Brazil (T.R.M., S.L.S.); Departamento de Bioquímica, Centro de Investigación y de Estudios Avanzados del IPN, México City, D.F., México (R.S
| | - Sandra Lauton Santos
- From the Signalisation et Physiopathologie Cardiovasculaire - UMR-S 1180, (T.R.M., G.A., D.F., G.R.-H., J.S., F.L., P.L., S.G., E.M., A.M.G., J.-P.B.), EA 4043 UBaPS (H.K.), and UMS-IPSIT, MIPSIT_Microscopy Facility (V.N.), Univ. Paris-Sud, INSERM, Université Paris-Saclay, 92296, Châtenay-Malabry, France; Department of Physiology, Federal University of Sergipe, Brazil (T.R.M., S.L.S.); Departamento de Bioquímica, Centro de Investigación y de Estudios Avanzados del IPN, México City, D.F., México (R.S
| | - Eric Morel
- From the Signalisation et Physiopathologie Cardiovasculaire - UMR-S 1180, (T.R.M., G.A., D.F., G.R.-H., J.S., F.L., P.L., S.G., E.M., A.M.G., J.-P.B.), EA 4043 UBaPS (H.K.), and UMS-IPSIT, MIPSIT_Microscopy Facility (V.N.), Univ. Paris-Sud, INSERM, Université Paris-Saclay, 92296, Châtenay-Malabry, France; Department of Physiology, Federal University of Sergipe, Brazil (T.R.M., S.L.S.); Departamento de Bioquímica, Centro de Investigación y de Estudios Avanzados del IPN, México City, D.F., México (R.S
| | - Angelica Rueda
- From the Signalisation et Physiopathologie Cardiovasculaire - UMR-S 1180, (T.R.M., G.A., D.F., G.R.-H., J.S., F.L., P.L., S.G., E.M., A.M.G., J.-P.B.), EA 4043 UBaPS (H.K.), and UMS-IPSIT, MIPSIT_Microscopy Facility (V.N.), Univ. Paris-Sud, INSERM, Université Paris-Saclay, 92296, Châtenay-Malabry, France; Department of Physiology, Federal University of Sergipe, Brazil (T.R.M., S.L.S.); Departamento de Bioquímica, Centro de Investigación y de Estudios Avanzados del IPN, México City, D.F., México (R.S
| | - Natalia López-Andrés
- From the Signalisation et Physiopathologie Cardiovasculaire - UMR-S 1180, (T.R.M., G.A., D.F., G.R.-H., J.S., F.L., P.L., S.G., E.M., A.M.G., J.-P.B.), EA 4043 UBaPS (H.K.), and UMS-IPSIT, MIPSIT_Microscopy Facility (V.N.), Univ. Paris-Sud, INSERM, Université Paris-Saclay, 92296, Châtenay-Malabry, France; Department of Physiology, Federal University of Sergipe, Brazil (T.R.M., S.L.S.); Departamento de Bioquímica, Centro de Investigación y de Estudios Avanzados del IPN, México City, D.F., México (R.S
| | - Ana Maria Gómez
- From the Signalisation et Physiopathologie Cardiovasculaire - UMR-S 1180, (T.R.M., G.A., D.F., G.R.-H., J.S., F.L., P.L., S.G., E.M., A.M.G., J.-P.B.), EA 4043 UBaPS (H.K.), and UMS-IPSIT, MIPSIT_Microscopy Facility (V.N.), Univ. Paris-Sud, INSERM, Université Paris-Saclay, 92296, Châtenay-Malabry, France; Department of Physiology, Federal University of Sergipe, Brazil (T.R.M., S.L.S.); Departamento de Bioquímica, Centro de Investigación y de Estudios Avanzados del IPN, México City, D.F., México (R.S
| | - Marc Lombès
- From the Signalisation et Physiopathologie Cardiovasculaire - UMR-S 1180, (T.R.M., G.A., D.F., G.R.-H., J.S., F.L., P.L., S.G., E.M., A.M.G., J.-P.B.), EA 4043 UBaPS (H.K.), and UMS-IPSIT, MIPSIT_Microscopy Facility (V.N.), Univ. Paris-Sud, INSERM, Université Paris-Saclay, 92296, Châtenay-Malabry, France; Department of Physiology, Federal University of Sergipe, Brazil (T.R.M., S.L.S.); Departamento de Bioquímica, Centro de Investigación y de Estudios Avanzados del IPN, México City, D.F., México (R.S
| | - Jean-Pierre Benitah
- From the Signalisation et Physiopathologie Cardiovasculaire - UMR-S 1180, (T.R.M., G.A., D.F., G.R.-H., J.S., F.L., P.L., S.G., E.M., A.M.G., J.-P.B.), EA 4043 UBaPS (H.K.), and UMS-IPSIT, MIPSIT_Microscopy Facility (V.N.), Univ. Paris-Sud, INSERM, Université Paris-Saclay, 92296, Châtenay-Malabry, France; Department of Physiology, Federal University of Sergipe, Brazil (T.R.M., S.L.S.); Departamento de Bioquímica, Centro de Investigación y de Estudios Avanzados del IPN, México City, D.F., México (R.S
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Ruhs S, Nolze A, Hübschmann R, Grossmann C. 30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Nongenomic effects via the mineralocorticoid receptor. J Endocrinol 2017; 234:T107-T124. [PMID: 28348113 DOI: 10.1530/joe-16-0659] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Accepted: 03/27/2017] [Indexed: 12/12/2022]
Abstract
The mineralocorticoid receptor (MR) belongs to the steroid hormone receptor family and classically functions as a ligand-dependent transcription factor. It is involved in water-electrolyte homeostasis and blood pressure regulation but independent from these effects also furthers inflammation, fibrosis, hypertrophy and remodeling in cardiovascular tissues. Next to genomic effects, aldosterone elicits very rapid actions within minutes that do not require transcription or translation and that occur not only in classical MR epithelial target organs like kidney and colon but also in nonepithelial tissues like heart, vasculature and adipose tissue. Most of these effects can be mediated by classical MR and its crosstalk with different signaling cascades. Near the plasma membrane, the MR seems to be associated with caveolin and striatin as well as with receptor tyrosine kinases like EGFR, PDGFR and IGF1R and G protein-coupled receptors like AT1 and GPER1, which then mediate nongenomic aldosterone effects. GPER1 has also been named a putative novel MR. There is a close interaction and functional synergism between the genomic and the nongenomic signaling so that nongenomic signaling can lead to long-term effects and support genomic actions. Therefore, understanding nongenomic aldosterone/MR effects is of potential relevance for modulating genomic aldosterone effects and may provide additional targets for intervention.
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Affiliation(s)
- Stefanie Ruhs
- Julius Bernstein Institute of PhysiologyMartin Luther University Halle-Wittenberg, Halle, Germany
| | - Alexander Nolze
- Julius Bernstein Institute of PhysiologyMartin Luther University Halle-Wittenberg, Halle, Germany
| | - Ralf Hübschmann
- Julius Bernstein Institute of PhysiologyMartin Luther University Halle-Wittenberg, Halle, Germany
| | - Claudia Grossmann
- Julius Bernstein Institute of PhysiologyMartin Luther University Halle-Wittenberg, Halle, Germany
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Salt-dependent Blood Pressure in Human Aldosterone Synthase-Transgenic Mice. Sci Rep 2017; 7:492. [PMID: 28352088 PMCID: PMC5412599 DOI: 10.1038/s41598-017-00461-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Accepted: 02/28/2017] [Indexed: 01/19/2023] Open
Abstract
Hypertension is one of the most important, preventable causes of premature morbidity and mortality in the developed world. Aldosterone is a major mineralocorticoid hormone that plays a key role in the regulation of blood pressure and is implicated in the pathogenesis of hypertension and heart failure. Aldosterone synthase (AS, cytochrome P450 11B2, cyp11B2) is the sole enzyme responsible for the production of aldosterone in humans. To determine the effects of increased expression of human aldosterone synthase (hAS) on blood pressure (BP), we established transgenic mice carrying the hAS gene (cyp11B2). We showed that hAS overexpression increased levels of aldosterone in hAS+/- mice. On high salt diet (HS), BPs of hAS+/- mice were significantly increased compared with WT mice. Fadrozole (an inhibitor of aldosterone synthase) treatment significantly reduced BPs of hAS+/- mice on HS. This is the first time overexpression of AS in a transgenic mouse line has shown an ability to induce HP. Specifically inhibiting AS activity in these mice is a promising therapy for reducing hypertension. This hAS transgenic mouse model is therefore an ideal animal model for hypertension therapy studies.
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Gray GA, White CI, Castellan RFP, McSweeney SJ, Chapman KE. Getting to the heart of intracellular glucocorticoid regeneration: 11β-HSD1 in the myocardium. J Mol Endocrinol 2017; 58:R1-R13. [PMID: 27553202 PMCID: PMC5148800 DOI: 10.1530/jme-16-0128] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2016] [Accepted: 08/19/2016] [Indexed: 12/11/2022]
Abstract
Corticosteroids influence the development and function of the heart and its response to injury and pressure overload via actions on glucocorticoid (GR) and mineralocorticoid (MR) receptors. Systemic corticosteroid concentration depends largely on the activity of the hypothalamic-pituitary-adrenal (HPA) axis, but glucocorticoid can also be regenerated from intrinsically inert metabolites by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), selectively increasing glucocorticoid levels within cells and tissues. Extensive studies have revealed the roles for glucocorticoid regeneration by 11β-HSD1 in liver, adipose, brain and other tissues, but until recently, there has been little focus on the heart. This article reviews the evidence for glucocorticoid metabolism by 11β-HSD1 in the heart and for a role of 11β-HSD1 activity in determining the myocardial growth and physiological function. We also consider the potential of 11β-HSD1 as a therapeutic target to enhance repair after myocardial infarction and to prevent the development of cardiac remodelling and heart failure.
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Affiliation(s)
- Gillian A Gray
- University/BHF Centre for Cardiovascular ScienceQueen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Christopher I White
- University/BHF Centre for Cardiovascular ScienceQueen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Raphael F P Castellan
- University/BHF Centre for Cardiovascular ScienceQueen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Sara J McSweeney
- University/BHF Centre for Cardiovascular ScienceQueen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Karen E Chapman
- University/BHF Centre for Cardiovascular ScienceQueen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
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Araujo CM, Hermidorff MM, Amancio GDCS, Lemos DDS, Silva ME, de Assis LVM, Isoldi MC. Rapid effects of aldosterone in primary cultures of cardiomyocytes - do they suggest the existence of a membrane-bound receptor? J Recept Signal Transduct Res 2015; 36:435-44. [PMID: 27305962 DOI: 10.3109/10799893.2015.1122042] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Aldosterone acts on its target tissue through a classical mechanism or through the rapid pathway through a putative membrane-bound receptor. Our goal here was to better understand the molecular and biochemical rapid mechanisms responsible for aldosterone-induced cardiomyocyte hypertrophy. We have evaluated the hypertrophic process through the levels of ANP, which was confirmed by the analysis of the superficial area of cardiomyocytes. Aldosterone increased the levels of ANP and the cellular area of the cardiomyocytes; spironolactone reduced the aldosterone-increased ANP level and cellular area of cardiomyocytes. Aldosterone or spironolactone alone did not increase the level of cyclic 3',5'-adenosine monophosphate (cAMP), but aldosterone plus spironolactone led to increased cAMP level; the treatment with aldosterone + spironolactone + BAPTA-AM reduced the levels of cAMP. These data suggest that aldosterone-induced cAMP increase is independent of mineralocorticoid receptor (MR) and dependent on Ca(2+). Next, we have evaluated the role of A-kinase anchor proteins (AKAP) in the aldosterone-induced hypertrophic response. We have found that St-Ht31 (AKAP inhibitor) reduced the increased level of ANP which was induced by aldosterone; in addition, we have found an increase on protein kinase C (PKC) and extracellular signal-regulated kinase 5 (ERK5) activity when cells were treated with aldosterone alone, spironolactone alone and with a combination of both. Our data suggest that PKC could be responsible for ERK5 aldosterone-induced phosphorylation. Our study suggests that the aldosterone through its rapid effects promotes a hypertrophic response in cardiomyocytes that is controlled by an AKAP, being dependent on ERK5 and PKC, but not on cAMP/cAMP-dependent protein kinase signaling pathways. Lastly, we provide evidence that the targeting of AKAPs could be relevant in patients with aldosterone-induced cardiac hypertrophy and heart failure.
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Affiliation(s)
- Carolina Morais Araujo
- a Laboratory of Hypertension , Research Center in Biological Science, Institute of Exact and Biological Sciences, Federal University of Ouro Preto , Ouro Preto , Brazil
| | - Milla Marques Hermidorff
- a Laboratory of Hypertension , Research Center in Biological Science, Institute of Exact and Biological Sciences, Federal University of Ouro Preto , Ouro Preto , Brazil
| | - Gabriela de Cassia Sousa Amancio
- a Laboratory of Hypertension , Research Center in Biological Science, Institute of Exact and Biological Sciences, Federal University of Ouro Preto , Ouro Preto , Brazil
| | - Denise da Silveira Lemos
- b Laboratory of Immunoparasitology , Center for Research in Biological Sciences, Institute of Biological and Exact Sciences, Federal University of Ouro Preto , Ouro Preto , Brazil
| | - Marcelo Estáquio Silva
- c Laboratory of Experimental Nutrition , School of Nutrition, Federal University of Ouro Preto , Ouro Preto , Brazil , and
| | | | - Mauro César Isoldi
- a Laboratory of Hypertension , Research Center in Biological Science, Institute of Exact and Biological Sciences, Federal University of Ouro Preto , Ouro Preto , Brazil
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Hwang MH, Yoo JK, Luttrell M, Kim HK, Meade TH, English M, Talcott S, Jaffe IZ, Christou DD. Acute effect of mineralocorticoid receptor antagonism on vascular function in healthy older adults. Exp Gerontol 2015; 73:86-94. [PMID: 26639352 DOI: 10.1016/j.exger.2015.11.017] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Revised: 11/04/2015] [Accepted: 11/26/2015] [Indexed: 12/27/2022]
Abstract
Mineralocorticoid receptor (MR) activation by aldosterone may regulate vascular function in health or contribute to vascular dysfunction in cardiovascular disease. Whether the effects are beneficial or detrimental to vascular function appear to be dependent on the integrity of the vascular endothelium and whether the responses are short-term or chronic. Acute modulation of MR activation has resulted in conflicting outcomes on vascular function in young healthy adults. Little is known about the vascular role of aldosterone and MR activation in healthy human aging. The primary objective of this study was to examine whether acute inhibition of MR by the selective antagonist eplerenone, influences vascular function in healthy older adults. We performed a randomized, double-blind, placebo-controlled crossover study in 22 adults (61±1 years; mean±SE, 53-79 years) who were free from overt clinical cardiovascular disease. We measured brachial artery flow-mediated endothelium-dependent dilation and endothelium-independent dilation to sublingual nitroglycerin (0.4 mg) following eplerenone (100 mg/dose, 2 doses, 24h between doses) or placebo. In response to acute MR antagonism, flow-mediated dilation decreased by 19% (from 6.9±0.5 to 5.6±0.6%, P=0.02; placebo vs. eplerenone). Endothelial nitric oxide synthase (eNOS) activity also decreased following MR antagonism based on the ratio of phosphorylated eNOS(Ser1177) to total eNOS (1.53±0.08 vs. 1.29±0.06, P=0.02). Nitroglycerin-induced dilation and blood pressure were unaffected (nitroglycerin-induced dilation: 21.9±1.9 vs. 21.0±1.5%, P=0.5 and systolic/diastolic blood pressure: 135/77±4/2 vs. 134/77±4/2 mmHg, P≥0.6). In conclusion, acute MR antagonism impairs vascular endothelial function in healthy older adults without influencing vascular smooth muscle responsiveness to exogenous nitric oxide or blood pressure.
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Affiliation(s)
- Moon-Hyon Hwang
- Dept of Applied Physiology & Kinesiology, University of Florida, Gainesville, FL, United States; Division of Health and Exercise Science, Incheon National University, Incheon, Korea
| | - Jeung-Ki Yoo
- Dept of Applied Physiology & Kinesiology, University of Florida, Gainesville, FL, United States
| | - Meredith Luttrell
- Dept of Human Physiology, University of Oregon, Eugene, OR, United States
| | - Han-Kyul Kim
- Dept of Applied Physiology & Kinesiology, University of Florida, Gainesville, FL, United States
| | - Thomas H Meade
- Dept of Cardiology, Baylor Scott & White Health, College Station, TX, United States; Texas A&M University Health Science Center, Bryan, TX, United States
| | - Mark English
- Dept of Family & Community Medicine, Baylor Scott & White Health, College Station, TX, United States
| | - Susanne Talcott
- Dept of Nutrition and Food Science and Dept of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, United States
| | - Iris Z Jaffe
- Molecular Cardiology Research Institute and Division of Cardiology, Department of Medicine, Tufts Medical Center, Boston, MA, United States
| | - Demetra D Christou
- Dept of Applied Physiology & Kinesiology, University of Florida, Gainesville, FL, United States.
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Ashton AW, Le TYL, Gomez-Sanchez CE, Morel-Kopp MC, McWhinney B, Hudson A, Mihailidou AS. Role of Nongenomic Signaling Pathways Activated by Aldosterone During Cardiac Reperfusion Injury. Mol Endocrinol 2015; 29:1144-55. [PMID: 26121234 DOI: 10.1210/me.2014-1410] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Aldosterone (Aldo) activates both genomic and nongenomic signaling pathways in the cardiovascular system. Activation of genomic signaling pathways contributes to the adverse cardiac actions of Aldo during reperfusion injury; however, the extent nongenomic signaling pathways contribute has been difficult to identify due to lack of a specific ligand that activates only nongenomic signaling pathways. Using a pegylated aldosterone analog, aldosterone-3-carboxymethoxylamine-TFP ester conjugated to methoxypegylated amine (Aldo-PEG), we are able for the first time to distinguish between nongenomic and genomic cardiac actions of Aldo. We confirm Aldo-PEG activates phosphorylation of ERK1/2 in rat cardiomyocyte H9c2 cells similar to Aldo and G protein-coupled receptor 30 (GPR30 or GPER) agonist G1. GPER antagonist, G36, but not mineralocorticoid receptor (MR) antagonist spironolactone, prevented ERK1/2 phosphorylation by Aldo, Aldo-PEG, and G1. The selective nongenomic actions of Aldo-PEG are confirmed, with Aldo-PEG increasing superoxide production in H9c2 cells to similar levels as Aldo but having no effect on subcellular localization of MR. Striatin serves as a scaffold for GPER and MR, with GPER antagonist G36, but not spironolactone, restoring MR-striatin complexes. Aldo-PEG had no effect on MR-dependent transcriptional activation, whereas Aldo increased transcript levels of serum-regulated kinase 1 and plasminogen activator inhibitor-1. Using our ex vivo experimental rat model of myocardial infarction, we found aggravated infarct size and apoptosis by Aldo but not Aldo-PEG. Our studies confirm that in the heart, activation of nongenomic signaling pathways alone are not sufficient to trigger the deleterious effects of aldosterone during myocardial reperfusion injury.
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Affiliation(s)
- Anthony W Ashton
- Cardiovascular and Hormonal Research Laboratory, Department of Cardiology (T.Y.L.L., A.S.M.), Division of Perinatal Research (A.W.A.), Northern Blood Research Centre and Department of Haematology and Transfusion Medicine (M.-C.M.-K.), Sydney Neuro-Oncology Group and Bill Walsh Translational Cancer Research Laboratory (A.H.), Royal North Shore Hospital and Kolling Institute (A.W.A., T.Y.L.L., M.-C.M.-K., A.H., A.S.M.), Royal North Shore Hospital and The University of Sydney, Sydney 2065, Australia; Division of Endocrinology, G. V. (Sonny) Montgomery Veterans Affairs Medical Center and University of Mississippi Medical Center (C.E.G.-S.), Jackson, Mississippi 39216; and Analytical Chemistry Unit (B.M.), Pathology Queensland, Health Services Support Agency, Royal Brisbane and Women's Hospital, Brisbane, Queensland 4029, Australia
| | - Thi Y L Le
- Cardiovascular and Hormonal Research Laboratory, Department of Cardiology (T.Y.L.L., A.S.M.), Division of Perinatal Research (A.W.A.), Northern Blood Research Centre and Department of Haematology and Transfusion Medicine (M.-C.M.-K.), Sydney Neuro-Oncology Group and Bill Walsh Translational Cancer Research Laboratory (A.H.), Royal North Shore Hospital and Kolling Institute (A.W.A., T.Y.L.L., M.-C.M.-K., A.H., A.S.M.), Royal North Shore Hospital and The University of Sydney, Sydney 2065, Australia; Division of Endocrinology, G. V. (Sonny) Montgomery Veterans Affairs Medical Center and University of Mississippi Medical Center (C.E.G.-S.), Jackson, Mississippi 39216; and Analytical Chemistry Unit (B.M.), Pathology Queensland, Health Services Support Agency, Royal Brisbane and Women's Hospital, Brisbane, Queensland 4029, Australia
| | - Celso E Gomez-Sanchez
- Cardiovascular and Hormonal Research Laboratory, Department of Cardiology (T.Y.L.L., A.S.M.), Division of Perinatal Research (A.W.A.), Northern Blood Research Centre and Department of Haematology and Transfusion Medicine (M.-C.M.-K.), Sydney Neuro-Oncology Group and Bill Walsh Translational Cancer Research Laboratory (A.H.), Royal North Shore Hospital and Kolling Institute (A.W.A., T.Y.L.L., M.-C.M.-K., A.H., A.S.M.), Royal North Shore Hospital and The University of Sydney, Sydney 2065, Australia; Division of Endocrinology, G. V. (Sonny) Montgomery Veterans Affairs Medical Center and University of Mississippi Medical Center (C.E.G.-S.), Jackson, Mississippi 39216; and Analytical Chemistry Unit (B.M.), Pathology Queensland, Health Services Support Agency, Royal Brisbane and Women's Hospital, Brisbane, Queensland 4029, Australia
| | - Marie-Christine Morel-Kopp
- Cardiovascular and Hormonal Research Laboratory, Department of Cardiology (T.Y.L.L., A.S.M.), Division of Perinatal Research (A.W.A.), Northern Blood Research Centre and Department of Haematology and Transfusion Medicine (M.-C.M.-K.), Sydney Neuro-Oncology Group and Bill Walsh Translational Cancer Research Laboratory (A.H.), Royal North Shore Hospital and Kolling Institute (A.W.A., T.Y.L.L., M.-C.M.-K., A.H., A.S.M.), Royal North Shore Hospital and The University of Sydney, Sydney 2065, Australia; Division of Endocrinology, G. V. (Sonny) Montgomery Veterans Affairs Medical Center and University of Mississippi Medical Center (C.E.G.-S.), Jackson, Mississippi 39216; and Analytical Chemistry Unit (B.M.), Pathology Queensland, Health Services Support Agency, Royal Brisbane and Women's Hospital, Brisbane, Queensland 4029, Australia
| | - Brett McWhinney
- Cardiovascular and Hormonal Research Laboratory, Department of Cardiology (T.Y.L.L., A.S.M.), Division of Perinatal Research (A.W.A.), Northern Blood Research Centre and Department of Haematology and Transfusion Medicine (M.-C.M.-K.), Sydney Neuro-Oncology Group and Bill Walsh Translational Cancer Research Laboratory (A.H.), Royal North Shore Hospital and Kolling Institute (A.W.A., T.Y.L.L., M.-C.M.-K., A.H., A.S.M.), Royal North Shore Hospital and The University of Sydney, Sydney 2065, Australia; Division of Endocrinology, G. V. (Sonny) Montgomery Veterans Affairs Medical Center and University of Mississippi Medical Center (C.E.G.-S.), Jackson, Mississippi 39216; and Analytical Chemistry Unit (B.M.), Pathology Queensland, Health Services Support Agency, Royal Brisbane and Women's Hospital, Brisbane, Queensland 4029, Australia
| | - Amanda Hudson
- Cardiovascular and Hormonal Research Laboratory, Department of Cardiology (T.Y.L.L., A.S.M.), Division of Perinatal Research (A.W.A.), Northern Blood Research Centre and Department of Haematology and Transfusion Medicine (M.-C.M.-K.), Sydney Neuro-Oncology Group and Bill Walsh Translational Cancer Research Laboratory (A.H.), Royal North Shore Hospital and Kolling Institute (A.W.A., T.Y.L.L., M.-C.M.-K., A.H., A.S.M.), Royal North Shore Hospital and The University of Sydney, Sydney 2065, Australia; Division of Endocrinology, G. V. (Sonny) Montgomery Veterans Affairs Medical Center and University of Mississippi Medical Center (C.E.G.-S.), Jackson, Mississippi 39216; and Analytical Chemistry Unit (B.M.), Pathology Queensland, Health Services Support Agency, Royal Brisbane and Women's Hospital, Brisbane, Queensland 4029, Australia
| | - Anastasia S Mihailidou
- Cardiovascular and Hormonal Research Laboratory, Department of Cardiology (T.Y.L.L., A.S.M.), Division of Perinatal Research (A.W.A.), Northern Blood Research Centre and Department of Haematology and Transfusion Medicine (M.-C.M.-K.), Sydney Neuro-Oncology Group and Bill Walsh Translational Cancer Research Laboratory (A.H.), Royal North Shore Hospital and Kolling Institute (A.W.A., T.Y.L.L., M.-C.M.-K., A.H., A.S.M.), Royal North Shore Hospital and The University of Sydney, Sydney 2065, Australia; Division of Endocrinology, G. V. (Sonny) Montgomery Veterans Affairs Medical Center and University of Mississippi Medical Center (C.E.G.-S.), Jackson, Mississippi 39216; and Analytical Chemistry Unit (B.M.), Pathology Queensland, Health Services Support Agency, Royal Brisbane and Women's Hospital, Brisbane, Queensland 4029, Australia
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23
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Therapeutic targeting of aldosterone: a novel approach to the treatment of glomerular disease. Clin Sci (Lond) 2015; 128:527-35. [PMID: 25671776 DOI: 10.1042/cs20140432] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Numerous studies have established a role for mineralocorticoids in the development of renal fibrosis. Originally, the research focus for mineralocorticoid-induced fibrosis was on the collecting duct, where 'classical' mineralocorticoid receptors (MRs) involved with electrolyte transport are present. Epithelial cells in this segment can, under selected circumstances, also respond to MR activation by initiating pro-fibrotic pathways. More recently, 'non-classical' MRs have been described in kidney cells not associated with electrolyte transport, including mesangial cells and podocytes within the glomerulus. Activation of MRs in these cells appears to lead to glomerular sclerosis. Mechanistically, aldosterone induces excess production of reactive oxygen species (ROS) and oxidative stress in glomerular cells through activation of NADPH oxidase. In mesangial cells, aldosterone also has pro-apoptotic, mitogenic and pro-fibrogenic effects, all of which potentially promote active remodelling and expansion of the mesangium. Although mitochondrial dysfunction seems to mediate the aldosterone-induced mesangial apoptosis, the ROS dependent epithelial growth factor receptor (EGFR) transactivation is probably responsible for aldosterone-induced mesangial mitosis and proliferation. In podocytes, mitochondrial dysfunction elicited by oxidative stress is an early event associated with aldosterone-induced podocyte injury. Both the p38 MAPK (p38 mitogen-activated protein kinase) signalling and the redox-sensitive glycogen synthase kinase (GSK)3β pathways are centrally implicated in aldosterone-induced podocyte death. Aldosterone-induced GSK3β over-activity could potentially cause hyperphosphorylation and over-activation of putative GSK3β substrates, including structural components of the mitochondrial permeability transition (MPT) pore, all of which lead to cell injury and death. Clinically, proteinuria significantly decreases when aldosterone inhibitors are included in the treatment of many glomerular diseases further supporting the view that mineralocorticoids are important players in glomerular pathology.
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24
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Güder G, Hammer F, Deutschbein T, Brenner S, Berliner D, Deubner N, Bidlingmaier M, Ertl G, Allolio B, Angermann CE, Fassnacht M, Störk S. Prognostic Value of Aldosterone and Cortisol in Patients Hospitalized for Acutely Decompensated Chronic Heart Failure With and Without Mineralocorticoid Receptor Antagonism. J Card Fail 2015; 21:208-16. [DOI: 10.1016/j.cardfail.2014.12.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2014] [Revised: 12/10/2014] [Accepted: 12/19/2014] [Indexed: 01/10/2023]
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Catena C, Colussi G, Sechi LA. Treatment of Primary Aldosteronism and Organ Protection. Int J Endocrinol 2015; 2015:597247. [PMID: 26074961 PMCID: PMC4449945 DOI: 10.1155/2015/597247] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Accepted: 03/31/2015] [Indexed: 12/25/2022] Open
Abstract
Primary aldosteronism is a frequent form of secondary hypertension that had long been considered relatively benign. Experimental and clinical evidence collected in the last two decades, however, has clearly demonstrated that this endocrine disorder is associated with excess cardiovascular and renal complications as compared to essential hypertension. These complications reflect the ability of inappropriate elevation of plasma aldosterone to cause tissue damage beyond that induced by high blood pressure itself, thereby setting the stage for major cardiovascular and renal disease. Because of the impact of elevated aldosterone on organ damage, goals of treatment in patients with primary aldosteronism should not be limited to normalization of blood pressure, and prevention or correction of organ complications is mandatory. Treatment with mineralocorticoid receptor antagonists or unilateral adrenalectomy is the respective options for treatment of idiopathic adrenal hyperplasia or aldosterone-producing adenoma. Last years have witnessed a rapid growth in knowledge concerning the effects of these treatments on cardiovascular and renal protection. This paper is an overview of the cardiovascular and renal complications that occur in patients with primary aldosteronism and a summary of the results that have been obtained in the long term on cardiovascular and renal outcomes with either medical or surgical treatment.
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Affiliation(s)
- Cristiana Catena
- Hypertension Unit, Internal Medicine, Department of Experimental and Clinical Medical Sciences, University of Udine, 33100 Udine, Italy
- *Cristiana Catena:
| | - GianLuca Colussi
- Hypertension Unit, Internal Medicine, Department of Experimental and Clinical Medical Sciences, University of Udine, 33100 Udine, Italy
| | - Leonardo A. Sechi
- Hypertension Unit, Internal Medicine, Department of Experimental and Clinical Medical Sciences, University of Udine, 33100 Udine, Italy
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26
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Ménard J, Rigel DF, Watson C, Jeng AY, Fu F, Beil M, Liu J, Chen W, Hu CW, Leung-Chu J, LaSala D, Liang G, Rebello S, Zhang Y, Dole WP. Aldosterone synthase inhibition: cardiorenal protection in animal disease models and translation of hormonal effects to human subjects. J Transl Med 2014; 12:340. [PMID: 25491597 PMCID: PMC4301837 DOI: 10.1186/s12967-014-0340-9] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Accepted: 11/22/2014] [Indexed: 01/31/2023] Open
Abstract
Background Aldosterone synthase inhibition provides the potential to attenuate both the mineralocorticoid receptor-dependent and independent actions of aldosterone. In vitro studies with recombinant human enzymes showed LCI699 to be a potent, reversible, competitive inhibitor of aldosterone synthase (Ki = 1.4 ± 0.2 nmol/L in humans) with relative selectivity over 11β-hydroxylase. Methods Hormonal effects of orally administered LCI699 were examined in rat and monkey in vivo models of adrenocorticotropic hormone (ACTH) and angiotensin-II-stimulated aldosterone release, and were compared with the mineralocorticoid receptor antagonist eplerenone in a randomized, placebo-controlled study conducted in 99 healthy human subjects. The effects of LCI699 and eplerenone on cardiac and renal sequelae of aldosterone excess were investigated in a double-transgenic rat (dTG rat) model overexpressing human renin and angiotensinogen. Results Rat and monkey in vivo models of stimulated aldosterone release predicted human dose– and exposure–response relationships, but overestimated the selectivity of LCI699 in humans. In the dTG rat model, LCI699 dose-dependently blocked increases in aldosterone, prevented development of cardiac and renal functional abnormalities independent of blood pressure changes, and prolonged survival. Eplerenone prolonged survival to a similar extent, but was less effective in preventing cardiac and renal damage. In healthy human subjects, LCI699 0.5 mg selectively reduced plasma and 24 h urinary aldosterone by 49 ± 3% and 39 ± 6% respectively (Day 1, mean ± SEM; P < 0.001 vs placebo), which was associated with natriuresis and an increase in plasma renin activity. Doses of LCI699 greater than 1 mg inhibited basal and ACTH-stimulated cortisol. Eplerenone 100 mg increased plasma and 24 h urinary aldosterone while stimulating natriuresis and increasing renin activity. In contrast to eplerenone, LCI699 increased the aldosterone precursor 11-deoxycorticosterone and urinary potassium excretion. Conclusions These results provide new insights into the cardiac and renal effects of inhibiting aldosterone synthase in experimental models and translation of the hormonal effects to humans. Selective inhibition of aldosterone synthase appears to be a promising approach to treat diseases associated with aldosterone excess. Electronic supplementary material The online version of this article (doi:10.1186/s12967-014-0340-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Joël Ménard
- Université Paris Descartes, Faculté de Médecine and INSERM/AP-HP Clinical Investigation Center, Georges Pompidou Hospital, Paris, France.
| | - Dean F Rigel
- Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
| | - Catherine Watson
- Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
| | - Arco Y Jeng
- Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. .,Current address: Golda Och Academy, 1418 Pleasant Valley Way, West Orange, NJ, 07052, USA.
| | - Fumin Fu
- Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
| | - Michael Beil
- Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
| | - Jing Liu
- Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
| | - Wei Chen
- Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
| | - Chii-Whei Hu
- Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
| | | | - Daniel LaSala
- Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
| | - Guiqing Liang
- Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
| | - Sam Rebello
- Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
| | - Yiming Zhang
- Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
| | - William P Dole
- Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
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27
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Mineralocorticoid receptors and the heart, multiple cell types and multiple mechanisms: a focus on the cardiomyocyte. Clin Sci (Lond) 2013; 125:409-21. [PMID: 23829554 DOI: 10.1042/cs20130050] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
MR (mineralocorticoid receptor) activation in the heart plays a central role in the development of cardiovascular disease, including heart failure. The MR is present in many cell types within the myocardium, including cardiomyocytes, macrophages and the coronary vasculature. The specific role of the MR in each of these cell types in the initiation and progression of cardiac pathophysiology is not fully understood. Cardiomyocyte MRs are increasingly recognized to play a role in regulating cardiac function, electrical conduction and fibrosis, through direct signal mediation and through paracrine MR-dependent activity. Although MR blockade in the heart is an attractive therapeutic option for the treatment of heart failure and other forms of heart disease, current antagonists are limited by side effects owing to MR inactivation in other tissues (including renal targets). This has led to increased efforts to develop therapeutics that are more selective for cardiac MRs and which may have reduced the occurrence of side effects in non-cardiac tissues. A major clinical consideration in the treatment of cardiovascular disease is of the differences between males and females in the incidence and outcomes of cardiac events. There is clinical evidence that female sensitivity to endogenous MRs is more pronounced, and experimentally that MR-targeted interventions may be more efficacious in females. Given that sex differences have been described in MR signalling in a range of experimental settings and that the MR and oestrogen receptor pathways share some common signalling intermediates, it is becoming increasingly apparent that the mechanisms of MRs need to be evaluated in a sex-selective manner. Further research targeted to identify sex differences in cardiomyocyte MR activation and signalling processes has the potential to provide the basis for the development of cardiac-specific MR therapies that may also be sex-specific.
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28
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Sasser WC, Robert SM, Carlo WF, Borasino S, Dabal RJ, Kirklin JK, Alten JA. Postoperative serum cortisol concentration and adrenal insufficiency in neonates undergoing open-heart surgery. World J Pediatr Congenit Heart Surg 2013; 3:214-20. [PMID: 23804777 DOI: 10.1177/2150135111431268] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND We sought to determine whether immediate postoperative serum cortisol concentration predicts adrenal insufficiency in neonates after cardiac surgery with cardiopulmonary bypass. We hypothesized that cortisol <10 µg/dL would be associated with increased catecholamine requirements and fluid resuscitation and would predict hemodynamic responsiveness to exogenous steroids. METHODS Retrospective study of 41 neonates was carried out for the levels of cortisol in the immediate postoperative period; of whom, 15 received steroids due to high levels of inotropic support. Laboratory and clinical outcomes were collected. RESULTS Median cortisol was 12 µg/dL (interquartile range: 5.2-27.4). Levels of cortisol <10 µg/dL was not associated with any clinical variable indicative of increased illness severity. Peak lactate (9.1 vs 11.8 mmol/L, P = .04) and maximum arteriovenous saturation difference ([Sao 2 - Svo 2] 28% vs 32%, P = .05) were both lower among patients with levels of cortisol <10 µg/dL. Six (40%) patients had a significant hemodynamic improvement within 24 hours after receiving steroids (responders), although there was no statistical difference between levels of cortisol in responders versus nonresponders. Level of cortisol was positively correlated with maximum lactate (P < .001), maximum Sao 2 - Svo 2 (P < .001), maximum inotrope score (P = .014), initial 24-hour fluid intake (P = .012), and time to negative fluid balance (P = .008) and was negatively correlated with initial 24-hour urine output (P < .001). CONCLUSIONS Low cortisol obtained in the immediate postoperative period is not associated with worse postoperative outcomes or predictive of steroid responsiveness. In contrast, elevated levels of cortisol are positively correlated with severity of illness. The use of an absolute cortisol threshold to identify adrenal insufficiency and/or guide steroid therapy in neonates after cardiac surgery is unjustified.
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Affiliation(s)
- William C Sasser
- Division of Critical Care, Department of Pediatrics, Division of Critical Care, University of Alabama at Birmingham, Birmingham, AL, USA
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29
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Tiberio L, Nascimbeni R, Villanacci V, Casella C, Fra A, Vezzoli V, Furlan L, Meyer G, Parrinello G, Baroni MD, Salerni B, Schiaffonati L. The decrease of mineralcorticoid receptor drives angiogenic pathways in colorectal cancer. PLoS One 2013; 8:e59410. [PMID: 23555666 PMCID: PMC3610652 DOI: 10.1371/journal.pone.0059410] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2012] [Accepted: 02/13/2013] [Indexed: 12/03/2022] Open
Abstract
Angiogenesis plays a crucial role in tumor growth and progression. Low expression of mineralocorticoid receptor (MR) in several malignant tumors correlates with disease recurrence and overall survival. Previous studies have shown that MR expression is decreased in colorectal cancer (CRC). Here we hypothesize that decreased MR expression can contribute to angiogenesis and poor patient survival in colorectal malignancies. In a cohort of CRC patients, we analyzed tumor MR expression, its correlation with tumor microvascular density and its impact on survival. Subsequently, we interrogated the role of MR in angiogenesis in an in vitro model, based on the colon cancer cell line HCT116, ingenierized to re-express a physiologically controlled MR. In CRC, decreased MR expression was associated with increased microvascular density and poor patient survival. In pchMR transfected HCT116, aldosterone or natural serum steroids largely inhibited mRNA expression levels of both VEGFA and its receptor 2/KDR. In CRC, MR activation may significantly decrease angiogenesis by directly inhibiting dysregulated VEGFA and hypoxia-induced VEGFA mRNA expression. In addition, MR activation attenuates the expression of the VEGF receptor 2/KDR, possibly dampening the activation of a VEGFA/KDR dependent signaling pathway important for the survival of tumor cells under hypoxic conditions.
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Affiliation(s)
- Laura Tiberio
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Riccardo Nascimbeni
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
- First Unit of General Surgery, Brescia City Hospital, Brescia, Italy
| | | | - Claudio Casella
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
- First Unit of General Surgery, Brescia City Hospital, Brescia, Italy
| | - Anna Fra
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Valeria Vezzoli
- Department of BioSciences, University of Milano, Milan, Italy
| | - Lucia Furlan
- Department of Clinical and Experimental Medicine, University of Padova, Padova, Italy
| | - Giuliano Meyer
- Department of BioSciences, University of Milano, Milan, Italy
| | - Giovanni Parrinello
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | | | - Bruno Salerni
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
- First Unit of General Surgery, Brescia City Hospital, Brescia, Italy
| | - Luisa Schiaffonati
- Department of Clinical and Experimental Medicine, University of Padova, Padova, Italy
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30
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Young MJ. Targeting the mineralocorticoid receptor in cardiovascular disease. Expert Opin Ther Targets 2013; 17:321-31. [DOI: 10.1517/14728222.2013.748750] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
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Ruhs S, Strätz N, Schlör K, Meinel S, Mildenberger S, Rabe S, Gekle M, Grossmann C. Modulation of transcriptional mineralocorticoid receptor activity by nitrosative stress. Free Radic Biol Med 2012; 53:1088-100. [PMID: 22749806 DOI: 10.1016/j.freeradbiomed.2012.06.028] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2012] [Revised: 05/29/2012] [Accepted: 06/19/2012] [Indexed: 11/18/2022]
Abstract
The mineralocorticoid receptor (MR) plays an important role in salt and water homeostasis and pathological tissue modifications, such as cardiovascular and renal fibrosis. Importantly, MR activation by aldosterone per se is not sufficient for the deleterious effects but requires the additional presence of a certain pathological milieu. Phenomenologically, this milieu could be generated by enhanced nitrosative stress. However, little is known regarding the modulation of MR transcriptional activity in a pathological milieu. The glucocorticoid receptor (GR), the closest relative of the MR, binds to the same hormone-response element but elicits protective effects on the cardiovascular system. To investigate the possible modulation of MR and GR by nitrosative stress under controlled conditions we used human embryonic kidney (HEK) cells and measured MR and GR transactivation after stimulation with the nitric oxide (NO)-donor SNAP and the peroxynitrite-donor Sin-1. In the presence of corticosteroids NO led to a general reduced corticosteroid receptor activity by repression of corticosteroid receptor-DNA interaction. The NO-induced diminished transcriptional MR activity was most pronounced during stimulation with physiological aldosterone concentrations, suggesting that NO treatment prevented its pathophysiological overactivation. In contrast, single peroxynitrite administration specifically induced the MR transactivation activity whereas genomic GR activity remained unchanged. Mechanistically, peroxynitrite permitted nuclear MR translocation whereas the cytosolic GR distribution was unaffected. Consequently, peroxynitrite represents a MR-specific aldosterone mimetic. In summary, our data indicate that the genomic function of corticosteroid receptors can be modulated by nitrosative stress which may induce the shift from physiological toward pathophysiological MR effects.
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Affiliation(s)
- Stefanie Ruhs
- Julius-Bernstein-Institut für Physiologie der Universität Halle-Wittenberg, Halle, Germany.
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32
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Wagman G, Fudim M, Kosmas CE, Panni RE, Vittorio TJ. The neurohormonal network in the RAAS can bend before breaking. Curr Heart Fail Rep 2012; 9:81-91. [PMID: 22528688 DOI: 10.1007/s11897-012-0091-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
The renin-angiotensin-aldosterone system (RAAS) has evolved in humans as one of the main physiological networks by which blood pressure and blood flow to vital organs is maintained. The RAAS has evolved to circumvent life-threatening events such as hemorrhage and starvation. Although short-term activation of this system had been well suited to counteract such catastrophes of early man, excessive chronic activation of the RAAS plays a fundamental role in the development and progression of cardiovascular disease in modern man. The RAAS is an intricate network comprising a number of major organ systems (heart, kidney, and vasculature) and signaling pathways. The main protagonists are renin, angiotensinogen (Ang), angiotensin I (Ang I), angiotensin II (Ang II), and aldosterone (Aldo). The study and delineation of each of these substances has allowed modern medicine to create targets by which cardiovascular disease can be treated. The main modulators that have been synthesized in this respect are angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), mineralocorticoid receptor blockers (MRBs), and direct renin inhibitors (DRIs). Over the past few decades, each of these substances has proven efficacious to varying degrees amongst a number of clinical settings. Additionally, there exists data for and against the use of these agents in combination. The use of these agents in combination poses a larger question conceptually: can excessive pharmacological inhibition of the RAAS lead to patient harm? This perspective will examine the concept of a neurohormonal inhibition ceiling in pertinent experimental and clinical trials.
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Affiliation(s)
- Gabriel Wagman
- St. Francis Hospital-The Heart Center, Division of Cardiology, Center for Advanced Cardiac Therapeutics, 100 Port Washington Boulevard, Roslyn, NY, 11576-1348, USA
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33
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Bienvenu LA, Morgan J, Rickard AJ, Tesch GH, Cranston GA, Fletcher EK, Delbridge LMD, Young MJ. Macrophage mineralocorticoid receptor signaling plays a key role in aldosterone-independent cardiac fibrosis. Endocrinology 2012; 153:3416-25. [PMID: 22653557 DOI: 10.1210/en.2011-2098] [Citation(s) in RCA: 95] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Mineralocorticoid receptor (MR) activation promotes the development of cardiac fibrosis and heart failure. Clinical evidence demonstrates that MR antagonism is protective even when plasma aldosterone levels are not increased. We hypothesize that MR activation in macrophages drives the profibrotic phenotype in the heart even when aldosterone levels are not elevated. The aim of the present study was to establish the role of macrophage MR signaling in mediating cardiac tissue remodeling caused by nitric oxide (NO) deficiency, a mineralocorticoid-independent insult. Male wild-type (MRflox/flox) and macrophage MR-knockout (MRflox/flox/LysMCre/+; mac-MRKO) mice were uninephrectomized, maintained on 0.9% NaCl drinking solution, with either vehicle (control) or the nitric oxide synthase (NOS) inhibitor NG-nitro-l-arginine methyl ester (L-NAME; 150 mg/kg/d) for 8 wk. NO deficiency increased systolic blood pressure at 4 wk in wild-type L-NAME/salt-treated mice compared with all other groups. At 8 wk, systolic blood pressure was increased above control in both L-NAME/salt treated wild-type and mac-MRKO mice by approximately 28 mm Hg by L-NAME/salt. Recruitment of macrophages was increased 2- to 3-fold in both L-NAME/salt treated wild-type and mac-MRKO. Inducible NOS positive macrophage infiltration and TNFα mRNA expression was greater in wild-type L-NAME/salt-treated mice compared with mac-MRKO, demonstrating that loss of MR reduces M1 phenotype. mRNA levels for markers of vascular inflammation and oxidative stress (NADPH oxidase 2, p22phox, intercellular adhesion molecule-1, G protein-coupled chemokine receptor 5) were similar in treated wild-type and mac-MRKO mice compared with control groups. In contrast, L-NAME/salt treatment increased interstitial collagen deposition in wild-type by about 33% but not in mac-MRKO mice. mRNA levels for connective tissue growth factor and collagen III were also increased above control treatment in wild-type (1.931 ± 0.215 vs. 1 ± 0.073) but not mac-MRKO mice (1.403 ± 0.150 vs. 1.286 ± 0.255). These data demonstrate that macrophage MR are necessary for the translation of inflammation and oxidative stress into interstitial and perivascular fibrosis after NO deficiency, even when plasma aldosterone is not elevated.
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34
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Groeneweg FL, Karst H, de Kloet ER, Joëls M. Mineralocorticoid and glucocorticoid receptors at the neuronal membrane, regulators of nongenomic corticosteroid signalling. Mol Cell Endocrinol 2012; 350:299-309. [PMID: 21736918 DOI: 10.1016/j.mce.2011.06.020] [Citation(s) in RCA: 202] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2011] [Revised: 06/15/2011] [Accepted: 06/20/2011] [Indexed: 02/06/2023]
Abstract
The balance between corticosteroid actions induced via activation of the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR) determines the brain's response to stress. While both receptors are best known for their delayed genomic role, it has become increasingly evident that they can also associate with the plasma membrane and act as mediators of rapid, nongenomic signalling. Nongenomic corticosteroid actions in the brain are required for the coordination of a rapid adaptive response to stress; membrane-associated MRs and GRs play a major role herein. However, many questions regarding the underlying mechanism are still unresolved. How do MR and GR translocate to the membrane and what are their downstream signalling partners? In this review we discuss these issues based on insights obtained from related receptors, most notably the estrogen receptor α.
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Affiliation(s)
- Femke L Groeneweg
- Department of Medical Pharmacology, Leiden Amsterdam Centre for Drug Research, Leiden University Medical Centre, Leiden University, Einsteinweg 55, Leiden, The Netherlands.
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35
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Calhoun DA, White WB, Krum H, Guo W, Bermann G, Trapani A, Lefkowitz MP, Ménard J. Effects of a Novel Aldosterone Synthase Inhibitor for Treatment of Primary Hypertension. Circulation 2011; 124:1945-55. [DOI: 10.1161/circulationaha.111.029892] [Citation(s) in RCA: 157] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Background—
LCI699, a novel inhibitor of aldosterone synthase, reduces serum aldosterone, and may have benefit in the treatment of hypertension.
Methods and Results—
We performed the first double-blind, randomized trial with LCI699 in patients with primary hypertension. We randomized 524 patients to LCI699 0.25 mg once daily (n=92), 0.5 mg once daily (n=88), 1.0 mg once daily (n=86), and 0.5 mg twice daily (n=97); eplerenone 50 mg twice daily (n=84); or placebo (n=77) for 8 weeks. Adrenocorticotropic hormone (250 μg IV) stimulation testing was performed in a subset of patients to quantify the selectivity of LCI699 for aldosterone synthase compared with 11-β-hydroxylase. Reductions in clinic diastolic blood pressure were significant for LCI699 1.0 mg (−7.1 mm Hg;
P
=0.0012) and eplerenone 50 mg twice daily (−7.9 mm Hg;
P
<0.0001) compared with placebo (−2.6 mm Hg) but not other doses of LCI699. Significant reductions in clinic systolic blood pressure were observed with all doses of LCI699 (
P
<0.005 or better) and eplerenone (
P
<0.0001). All doses of LCI699 significantly reduced 24-hour ambulatory blood pressure compared with placebo (
P
<0.01). Adrenocorticotropic hormone stimulation of cortisol was suppressed in ≈20% of subjects receiving LCI699 at a total daily dose of 1.0 mg. Safety and tolerability were similar among LCI699, placebo, and eplerenone.
Conclusions—
Aldosterone synthase inhibition with LCI699 significantly lowered clinic and ambulatory blood pressure. A minority of subjects developed blunted adrenocorticotropic hormone–stimulated release of cortisol. These results support additional research to evaluate use of aldosterone synthase inhibition in primary hypertension and/or patients characterized by aldosterone excess.
Clinical Trial Registration—
URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00758524.
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Affiliation(s)
- David A. Calhoun
- From the Vascular Biology and Hypertension Program, University of Alabama at Birmingham (D.A.C.); Division of Hypertension and Clinical Pharmacology, Pat and Jim Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington (W.B.W.); Center of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia (H.K.); Novartis Pharmaceuticals Corporation, East Hanover, NJ (W.G., A.T., M.P.L.)
| | - William B. White
- From the Vascular Biology and Hypertension Program, University of Alabama at Birmingham (D.A.C.); Division of Hypertension and Clinical Pharmacology, Pat and Jim Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington (W.B.W.); Center of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia (H.K.); Novartis Pharmaceuticals Corporation, East Hanover, NJ (W.G., A.T., M.P.L.)
| | - Henry Krum
- From the Vascular Biology and Hypertension Program, University of Alabama at Birmingham (D.A.C.); Division of Hypertension and Clinical Pharmacology, Pat and Jim Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington (W.B.W.); Center of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia (H.K.); Novartis Pharmaceuticals Corporation, East Hanover, NJ (W.G., A.T., M.P.L.)
| | - Weinong Guo
- From the Vascular Biology and Hypertension Program, University of Alabama at Birmingham (D.A.C.); Division of Hypertension and Clinical Pharmacology, Pat and Jim Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington (W.B.W.); Center of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia (H.K.); Novartis Pharmaceuticals Corporation, East Hanover, NJ (W.G., A.T., M.P.L.)
| | - Georgina Bermann
- From the Vascular Biology and Hypertension Program, University of Alabama at Birmingham (D.A.C.); Division of Hypertension and Clinical Pharmacology, Pat and Jim Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington (W.B.W.); Center of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia (H.K.); Novartis Pharmaceuticals Corporation, East Hanover, NJ (W.G., A.T., M.P.L.)
| | - Angelo Trapani
- From the Vascular Biology and Hypertension Program, University of Alabama at Birmingham (D.A.C.); Division of Hypertension and Clinical Pharmacology, Pat and Jim Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington (W.B.W.); Center of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia (H.K.); Novartis Pharmaceuticals Corporation, East Hanover, NJ (W.G., A.T., M.P.L.)
| | - Martin P. Lefkowitz
- From the Vascular Biology and Hypertension Program, University of Alabama at Birmingham (D.A.C.); Division of Hypertension and Clinical Pharmacology, Pat and Jim Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington (W.B.W.); Center of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia (H.K.); Novartis Pharmaceuticals Corporation, East Hanover, NJ (W.G., A.T., M.P.L.)
| | - Joël Ménard
- From the Vascular Biology and Hypertension Program, University of Alabama at Birmingham (D.A.C.); Division of Hypertension and Clinical Pharmacology, Pat and Jim Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington (W.B.W.); Center of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia (H.K.); Novartis Pharmaceuticals Corporation, East Hanover, NJ (W.G., A.T., M.P.L.)
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36
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Krug AW, Pojoga LH, Williams GH, Adler GK. Cell Membrane–Associated Mineralocorticoid Receptors? Hypertension 2011; 57:1019-25. [DOI: 10.1161/hypertensionaha.110.159459] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Alexander W. Krug
- From the Brigham and Women's Hospital/Harvard Medical School, Department of Endocrinology, Diabetes, and Hypertension, Boston, MA
| | - Luminita H. Pojoga
- From the Brigham and Women's Hospital/Harvard Medical School, Department of Endocrinology, Diabetes, and Hypertension, Boston, MA
| | - Gordon H. Williams
- From the Brigham and Women's Hospital/Harvard Medical School, Department of Endocrinology, Diabetes, and Hypertension, Boston, MA
| | - Gail K. Adler
- From the Brigham and Women's Hospital/Harvard Medical School, Department of Endocrinology, Diabetes, and Hypertension, Boston, MA
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37
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Essick EE, Sam F. Cardiac hypertrophy and fibrosis in the metabolic syndrome: a role for aldosterone and the mineralocorticoid receptor. Int J Hypertens 2011; 2011:346985. [PMID: 21747976 PMCID: PMC3124304 DOI: 10.4061/2011/346985] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2011] [Accepted: 03/07/2011] [Indexed: 12/28/2022] Open
Abstract
Obesity and hypertension, major risk factors for the metabolic syndrome, render individuals susceptible to an increased risk of cardiovascular complications, such as adverse cardiac remodeling and heart failure. There has been much investigation into the role that an increase in the renin-angiotensin-aldosterone system (RAAS) plays in the pathogenesis of metabolic syndrome and in particular, how aldosterone mediates left ventricular hypertrophy and increased cardiac fibrosis via its interaction with the mineralocorticoid receptor (MR). Here, we review the pertinent findings that link obesity with elevated aldosterone and the development of cardiac hypertrophy and fibrosis associated with the metabolic syndrome. These studies illustrate a complex cross-talk between adipose tissue, the heart, and the adrenal
cortex. Furthermore, we discuss findings from our laboratory that suggest that cardiac hypertrophy and fibrosis in the metabolic syndrome may involve cross-talk between aldosterone and adipokines (such as adiponectin).
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Affiliation(s)
- Eric E Essick
- Whitaker Cardiovascular Institute, Boston University School of Medicine 715 Albany Street, W507 Boston, MA 02118, USA
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38
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Aldosterone and mineralocorticoid receptor antagonists modulate elastin and collagen deposition in human skin. J Invest Dermatol 2010; 130:2396-406. [PMID: 20535129 DOI: 10.1038/jid.2010.155] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
We have shown that the steroid hormone aldosterone, recognized for its action on the kidney and the cardiovascular system, also modulates deposition of extracellular matrix in human skin. We have shown that treatment of primary cultures of normal skin fibroblasts with aldosterone (10 n-1 μM), in addition to stimulation of collagen type I expression, induces elastin gene expression and elastic fiber deposition. We have further shown that the elastogenic effect of aldosterone, which can be enhanced in the presence of mineralocorticoid receptor (MR) antagonists spironolactone and eplerenone, is executed in a MR-independent manner via amplification of IGF-I receptor-mediated signaling. Because aldosterone applied alone stimulates both collagen and elastin deposition in cultures of fibroblasts and in cultures of skin explants derived from dermal stretch marks, we postulate that this steroid should be used in the treatment of damaged skin that loses its volume and elasticity. Moreover, aldosterone applied in conjunction with spironolactone or eplerenone induces matrix remodeling and exclusively enhances elastogenesis in cultures of fibroblasts and explants derived from dermal scars and keloids. We therefore propose that intra-lesional injection of these factors should be considered in therapy for disfiguring dermal lesions and especially in prevention of their recurrence after surgical excision.
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39
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Abstract
Alteration of neurohormonal homeostasis is a hallmark of the pathophysiology of chronic heart failure (CHF). In particular, overactivation of the renin-angiotensin-aldosterone system and the sympathetic catecholaminergic system is consistently observed. Chronic overactivation of these hormonal pathways leads to a detrimental arrhythmogenic remodeling of cardiac tissue due to dysregulation of cardiac ion channels. Sudden cardiac death resulting from ventricular arrhythmias is a major cause of mortality in patients with CHF. All the drug classes known to reduce mortality in patients with CHF are neurohormonal blockers. The aim of this review was to provide an overview of how cardiac ion channels are regulated by hormones known to play a central role in the pathogenesis of CHF.
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40
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Grossmann C, Gekle M. New aspects of rapid aldosterone signaling. Mol Cell Endocrinol 2009; 308:53-62. [PMID: 19549592 DOI: 10.1016/j.mce.2009.02.005] [Citation(s) in RCA: 90] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2008] [Revised: 01/22/2009] [Accepted: 02/17/2009] [Indexed: 12/20/2022]
Abstract
Aldosterone, the endogenous ligand of the mineralocorticoid receptor (MR) in humans, is a steroid hormone that regulates salt and water homeostasis. Recently, additional pathophysiological effects in the renocardiovascular system have been identified. Besides genomic effects mediated by activated MR, rapid aldosterone actions that are independent of translation and transcription have been documented. While these nongenomic actions influence electrolyte homeostasis, pH and cell volume in classical MR target organs, they also participate in pathophysiological effects in the renocardiovascular system causing endothelial dysfunction, inflammation and remodeling. The mechanisms conveying these rapid effects consist of a multitude of signaling molecules and include a cross-talk with genomic aldosterone effects as well as with angiotensin II and epidermal growth factor receptor signaling. Rapid corticosteroid signaling via the MR has also been demonstrated in the brain. Altogether, the function of nongenomic aldosterone effects seems to be to modulate other signaling cascades, depending on the surrounding milieu.
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Affiliation(s)
- C Grossmann
- Julius-Bernstein-Institut für Physiologie, Universität Halle-Wittenberg, Halle/Saale, Germany.
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41
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Wenzel S, Tastan I, Abdallah Y, Schreckenberg R, Schlüter KD. Aldosterone improves contractile function of adult rat ventricular cardiomyocytes in a non-acute way: potential relationship to the calcium paradox of aldosteronism. Basic Res Cardiol 2009; 105:247-56. [PMID: 19763404 DOI: 10.1007/s00395-009-0059-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2009] [Revised: 08/19/2009] [Accepted: 08/21/2009] [Indexed: 10/20/2022]
Abstract
Heart failure is accompanied by electrolyte disturbance including reduced calcium and sodium in the extracellular milieu but increased calcium within cells, a phenomenon called "calcium paradox". Aldosteronism is considered as part of this disorder. Aldosterone antagonism is known to reduce cardiac mortality on top of standard therapies such as antagonism of the renin-angiotensin-system. However, the effect of aldosterone on cardiac function under basal conditions and conditions more closely related to those seen in heart failure remains elusive. In order to address this question the function of isolated cardiomyocytes was determined as unloaded cell shortening. Cardiomyocytes were isolated from adult rat hearts and cultured for 24 h in the presence of aldosterone. Thereafter, cell shortening was determined in cells that were electrically paced (0.5-2.0 Hz). The effect of aldosterone on cell shortening was investigated under basal and maximal inotropic stimulation, preincubation with angiotensin II and myocytes from spontaneously hypertensive rats. The composition of the culture medium was modified according to the extracellular milieu found in patients with end-stage heart failure. Aldosterone increased cell shortening in a frequency-dependent way under basal conditions and conditions of low calcium. It potentiated the effect of beta-adrenoceptor stimulation, increased the formation of oxygen radicals, and increased diastolic and systolic calcium. In conclusion, chronic exposure to aldosterone improves the function of cardiomyocytes under basal conditions and electrolyte disturbances that mimic the situation found in heart failure patients.
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Affiliation(s)
- Sibylle Wenzel
- Physiologisches Institut, Justus-Liebig-University Giessen, Aulweg 129, 35392 Giessen, Germany
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42
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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; 54:537-43. [DOI: 10.1161/hypertensionaha.109.131110] [Citation(s) in RCA: 242] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Increased mineralocorticoid levels plus high salt promote vascular inflammation and cardiac tissue remodeling. Mineralocorticoid receptors are expressed in many cell types of the cardiovascular system, including monocytes/macrophages and other inflammatory cell types. Although mineralocorticoid receptors are expressed in monocytes/macrophages, their role in regulating macrophage function to date has not been investigated. We, thus, used the Cre/LoxP-recombination system to selectively delete mineralocorticoid receptors from monocytes/macrophages with the lysozyme M promoter used to drive Cre expression (MR
flox/flox
/LysM
Cre/−
mice). Male mice from each genotype (MR
flox/flox
or wild-type and MR
flox/flox
/LysM
Cre/−
mice) were uninephrectomized, given 0.9% NaCl solution to drink, and treated for 8 days or 8 weeks with either vehicle (n=10) or deoxycorticosterone (n=10). Equivalent tissue macrophage numbers were seen for deoxycorticosterone treatment of each genotype at 8 days; in contrast, plasminogen activator inhibitor type 1 and NAD(P)H oxidase subunit 2 levels were increased in wild-type but not in MR
flox/flox
/LysM
Cre/−
mice given deoxycorticosterone. Baseline expression of other inflammatory genes was reduced in MR
flox/flox
/LysM
Cre/−
mice compared with wild-type mice. At 8 weeks, deoxycorticosterone-induced macrophage recruitment and connective tissue growth factor and plasminogen activator inhibitor type 1 mRNA levels were similar for each genotype; in contrast, MR
flox/flox
/LysM
Cre/−
mice showed no increase in cardiac fibrosis or blood pressure, as was seen in wild-type mice at 8 weeks. These data demonstrate the following points: (1) mineralocorticoid receptor signaling regulates basal monocyte/macrophage function; (2) macrophage recruitment is not altered by loss of mineralocorticoid receptor signaling in these cells; and (3) a novel and significant role is seen for macrophage signaling in the regulation of cardiac remodeling and systolic blood pressure in the deoxycorticosterone/salt model.
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Affiliation(s)
- Amanda J. Rickard
- From the Prince Henry’s Institute of Medical Research (A.J.R., J.M., J.W.F., P.J.F., M.J.Y.) and Department of Nephrology, Monash Medical Centre (G.T.), and Department of Physiology (A.J.R., M.J.Y.), Monash University, Clayton, Australia
| | - James Morgan
- From the Prince Henry’s Institute of Medical Research (A.J.R., J.M., J.W.F., P.J.F., M.J.Y.) and Department of Nephrology, Monash Medical Centre (G.T.), and Department of Physiology (A.J.R., M.J.Y.), Monash University, Clayton, Australia
| | - Greg Tesch
- From the Prince Henry’s Institute of Medical Research (A.J.R., J.M., J.W.F., P.J.F., M.J.Y.) and Department of Nephrology, Monash Medical Centre (G.T.), and Department of Physiology (A.J.R., M.J.Y.), Monash University, Clayton, Australia
| | - John W. Funder
- From the Prince Henry’s Institute of Medical Research (A.J.R., J.M., J.W.F., P.J.F., M.J.Y.) and Department of Nephrology, Monash Medical Centre (G.T.), and Department of Physiology (A.J.R., M.J.Y.), Monash University, Clayton, Australia
| | - Peter J. Fuller
- From the Prince Henry’s Institute of Medical Research (A.J.R., J.M., J.W.F., P.J.F., M.J.Y.) and Department of Nephrology, Monash Medical Centre (G.T.), and Department of Physiology (A.J.R., M.J.Y.), Monash University, Clayton, Australia
| | - Morag J. Young
- From the Prince Henry’s Institute of Medical Research (A.J.R., J.M., J.W.F., P.J.F., M.J.Y.) and Department of Nephrology, Monash Medical Centre (G.T.), and Department of Physiology (A.J.R., M.J.Y.), Monash University, Clayton, Australia
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43
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Chaggar PS, Malkin CJ, Shaw SM, Williams SG, Channer KS. Neuroendocrine Effects on the Heart and Targets for Therapeutic Manipulation in Heart Failure. Cardiovasc Ther 2009; 27:187-93. [DOI: 10.1111/j.1755-5922.2009.00094.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
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44
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Reini SA, Wood CE, Keller-Wood M. The ontogeny of genes related to ovine fetal cardiac growth. Gene Expr Patterns 2009; 9:122-8. [PMID: 18835462 PMCID: PMC2652708 DOI: 10.1016/j.gep.2008.09.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2008] [Revised: 09/06/2008] [Accepted: 09/12/2008] [Indexed: 02/02/2023]
Abstract
The objective of this study was to determine the ontogenetic profiles in left and right ventricle of genes implicated in cardiac growth, including mineralocorticoid (MR) and glucocorticoid (GR) receptor, 11 beta-hydroxysteroid dehydrogenase (11beta-HSD) 1 and 2 and genes of the angiotensin system and insulin-like growth factor (IGF) family. Samples from left and right ventricles (LV, RV) were collected from hearts of sheep fetuses at 80, 100, 120, 130, and 145 days of gestation and from newborn lambs. Quantitative real-time PCR was performed to determine the MR, GR, 11beta-HSD 1 and 2, angiotensin converting enzyme (ACE) 1 and 2, IGF1, IGF2, IGF receptors IGF-1R and IGF-2R, and IGF-binding proteins (IGFBP) 2 and 3. In the LV, MR and GR both decreased toward term. In the RV, MR and GR expression did not decrease, but both 11beta-HSD 1 and 2 mRNA levels increased after birth. ACE1 expression in LV and RV sharply increases just before parturition, whereas ACE2 decreased in the LV and RV in late gestation. IGF2, IGF2R, and IGFBP2 expression levels substantially decreased in late gestation in LV and RV; IGF2R also decreased with age in LV. These patterns suggest that reduced expression of genes related to IGF and angiotensin II action occur as proliferative activity declines and terminal differentiation occurs in the late gestation fetal heart.
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Affiliation(s)
- Seth A. Reini
- Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Charles E. Wood
- Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Maureen Keller-Wood
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32610-0487, USA
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Odermatt A, Atanasov AG. Mineralocorticoid receptors: emerging complexity and functional diversity. Steroids 2009; 74:163-71. [PMID: 19022273 DOI: 10.1016/j.steroids.2008.10.010] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2008] [Revised: 10/18/2008] [Accepted: 10/20/2008] [Indexed: 12/29/2022]
Abstract
Mineralocorticoid receptor (MR) activation in renal epithelial cells in response to the binding of aldosterone has long been implicated in the maintenance of body salt and fluid homeostasis and blood pressure control. 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) is believed to confer specificity on aldosterone to activate MR by inactivating 11beta-hydroxyglucocorticoids (corticosterone, cortisol) that are 100-1000 times more abundant in plasma than aldosterone and that can also bind and activate MR. Increasing evidence, however, challenges such a simple view of MR activation as well as its interaction with glucocorticoids and 11beta-HSDs. In non-epithelial tissues including brain, cardiomyocytes and macrophages, 11beta-hydroxyglucocorticoids seem to act as MR antagonists, and redox changes and signaling events may play pivotal roles for receptor activation in these tissues. This review addresses the emerging new view of the complex mechanisms underlying MR specificity of action, with a diversity of physiological roles and functions in different mineralocorticoid-responsive tissues.
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Affiliation(s)
- Alex Odermatt
- Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland.
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Arterial stiffness, intima-media thickness and carotid artery fibrosis in patients with primary aldosteronism. J Hypertens 2008; 26:2399-405. [DOI: 10.1097/hjh.0b013e32831286fd] [Citation(s) in RCA: 99] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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47
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Tang EHC, Vanhoutte PM. Gap junction inhibitors reduce endothelium-dependent contractions in the aorta of spontaneously hypertensive rats. J Pharmacol Exp Ther 2008; 327:148-53. [PMID: 18632992 DOI: 10.1124/jpet.108.140046] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Experiments were designed to determine the effect of gap junction inhibitors on endothelium-dependent contractions. Isolated aortic rings of spontaneously hypertensive rats (SHR) were suspended in vitro for isometric force recording. The nonselective gap junction inhibitor, carbenoxolone, reduced endothelium-dependent contractions to acetylcholine and the calcium ionophore A23187 [5-methylamino-2-(2S,3R,5R,8S,9S)-3,5,9-trimethyl-2-(1-oxo-(1H-pyrrol-2-yl)propan-2-yl)-1,7-dioxaspiro-(5,5)undecan-8-yl)methyl)benzooxazole-4-carboxylic acid]. There was no or modest effect of the gap peptides (40)Gap27, (37,43)Gap27, or (43)Gap26 when applied alone on endothelium-dependent contractions. However, the combined treatment with the three gap peptides significantly decreased endothelium-dependent contractions. The combined inhibition of the three connexins was not as effective as carbenoxolone, suggesting the involvement of other connexins in the process of endothelium-dependent contraction. The present study shows the involvement of gap junctions in endothelium-dependent contractions of the SHR aorta, presumably that of the combination of connexins 37, 40, and 43 rather than a single subtype of these proteins. Contractions of the vascular smooth muscle caused by 9,11-dideoxy-11alpha, 9alpha-epoxymethanoprostaglandin F(2alpha) (U46619) and prostacyclin, but not to those of endoperoxides and phenylephrine, were reduced only minimally by carbenoxolone. Thus, if gap junction signaling is involved in the contraction of the vascular smooth muscle to thromboxane-prostanoid receptor agonists, their contribution is small. This suggests that the reduction of endothelium-dependent contractions by carbenoxolone and the gap peptides cannot be attributed to the homocellular gap junctions between vascular smooth muscle, but is more likely to involve the homocellular gap junctions between endothelial cells and/or myoendothelial gap junctions.
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Affiliation(s)
- Eva H C Tang
- Department of Pharmacology, The University of Hong Kong, 21 Sassoon Rd., Pokfulam, Hong Kong, China
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Rossier MF, Lenglet S, Vetterli L, Python M, Maturana A. Corticosteroids and redox potential modulate spontaneous contractions in isolated rat ventricular cardiomyocytes. Hypertension 2008; 52:721-8. [PMID: 18695149 DOI: 10.1161/hypertensionaha.108.114223] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
The mineralocorticoid receptor has been implicated in the development of several cardiac pathologies and could participate in the high incidence of lethal ventricular arrhythmias associated with hyperaldosteronism. We have observed previously that aldosterone markedly increases in vitro the rate of spontaneous contractions of isolated neonate rat ventricular myocytes, a putative proarrhythmogenic condition if occurring in vivo. In the present study, we investigated the effect of glucocorticoids, the involvement of the glucocorticoid receptor, and the modulation of their action by redox agents. Aldosterone and glucocorticoids exerted in vitro a similar, concentration-dependent chronotropic action on cardiomyocytes, which was mediated by both the mineralocorticoid and glucocorticoid receptors. However, the relative contribution of each receptor was different for each agonist, at each concentration. Angiotensin II induced a similar response that was entirely dependent on the activity of the glucocorticoid receptor. Corticosteroid action was modulated by the redox state of the cells, with oxidation increasing the response while reducing conditions partially preventing it. When only the mineralocorticoid receptor was functionally present in the cells, oxidation was necessary to reveal glucocorticoid action, but no obvious competition with mineralocorticoids was observed when both agonists where simultaneously present. In conclusion, corticosteroids exert a strong chronotropic action in ventricular cardiomyocytes, mediated by both the mineralocorticoid and glucocorticoid receptors and modulated by the redox state of the cell. This phenomenon is believed to be because of cell electric remodeling and could contribute in vivo to the deleterious consequence of inappropriate receptor activation, leading to increased susceptibility of patients to arrhythmias.
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Affiliation(s)
- Michel F Rossier
- Department of Internal Medicine,Division of Endocrinology and Diabetology, University Hospital of Geneva, Geneva, Switzerland.
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Reini SA, Dutta G, Wood CE, Keller-Wood M. Cardiac corticosteroid receptors mediate the enlargement of the ovine fetal heart induced by chronic increases in maternal cortisol. J Endocrinol 2008; 198:419-27. [PMID: 18495945 PMCID: PMC2742944 DOI: 10.1677/joe-08-0022] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Previous studies have demonstrated that modest, physiologically relevant increases in maternal cortisol in late gestation result in enlargement of the fetal heart. In this study, we investigated the role of mineralocorticoid receptor (MR) or glucocorticoid receptor (GR) in this enlargement. Ewes with single fetuses were randomly assigned at approximately 120 days of gestation to one of four groups: maternal cortisol infusion (1 mg/kg per day, cortisol); maternal cortisol infusion with fetal intrapericardial infusion of the MR antagonist (MRa) potassium canrenoate (600 microg/day; cortisol+MRa); maternal cortisol infusion with fetal intrapericardial infusion of the GR antagonist (GRa) mifepristone (50 microg/day, cortisol+GRa); and maternal saline infusion (control). At approximately 130 days of gestation, fetal heart to body weight ratio and right ventricular (RV) and left ventricular (LV) free wall thicknesses were increased in the cortisol group when compared with control group. Fetal hearts from the cortisol+MRa group weighed significantly less, with thinner LV, RV, and interventricular septum walls, when compared with the cortisol group. Fetal hearts from the cortisol+GRa group had significantly thinner RV walls than the cortisol group. Fetal arterial pressure and heart rate were not different among groups at 130 days. Picrosirius red staining of fetal hearts indicated that the increased size was not accompanied by cardiac fibrosis. These results suggest that physiologic increases in maternal cortisol in late gestation induce fetal cardiac enlargement via MR and, to a lesser extent, by GR, and indicate that the enlargement is not secondary to an increase in fetal blood pressure or an increase in fibrosis within the fetal heart.
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Affiliation(s)
- Seth A. Reini
- Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL
| | - Garima Dutta
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL
| | - Charles E. Wood
- Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL
| | - Maureen Keller-Wood
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL
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Atkinson HC, Wood SA, Castrique ES, Kershaw YM, Wiles CCR, Lightman SL. Corticosteroids mediate fast feedback of the rat hypothalamic-pituitary-adrenal axis via the mineralocorticoid receptor. Am J Physiol Endocrinol Metab 2008; 294:E1011-22. [PMID: 18349112 DOI: 10.1152/ajpendo.00721.2007] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
The aim of this study was to investigate fast corticosteroid feedback of the hypothalamic-pituitary-adrenal (HPA) axis under basal conditions, in particular the role of the mineralocorticoid receptor. Blood samples were collected every 5 min from conscious rats at the diurnal peak, using an automated blood sampling system, and assayed for corticosterone. Feedback inhibition by rapidly increasing concentrations of ligand was achieved with an intravenous bolus of exogenous corticosteroid. This resulted in a significant reduction in plasma corticosterone concentrations within 23 min of the aldosterone bolus and 28 min of methylprednisolone. Evaluation of the pulsatile secretion of corticosterone revealed that the secretory event in progress at the time of administration of exogenous steroid was unaffected, whereas the next secretory event was inhibited by both aldosterone and methylprednisolone. The inhibitory effect of aldosterone was limited in duration (1 secretory event only), whereas that of methylprednisolone persisted for 4-5 h. Intravenous administration of canrenoate (a mineralocorticoid receptor antagonist) also had rapid effects on the HPA axis, with an elevation of ACTH within 10 min and corticosterone within 20 min. The inhibitory effect of aldosterone was unaffected by pretreatment with the glucocorticoid receptor antagonist RU-38486 but blocked by the canrenoate. These data imply an important role for the mineralocorticoid receptor in fast feedback of basal HPA activity and suggest that mineralocorticoids can dynamically regulate basal corticosterone concentrations during the diurnal peak, a time of day when there is already a high level of occupancy of the cytoplasmic mineralocorticoid receptor.
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Affiliation(s)
- Helen C Atkinson
- Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, UK.
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