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Roth L, Dogan S, Tuna BG, Aranyi T, Benitez S, Borrell-Pages M, Bozaykut P, De Meyer GRY, Duca L, Durmus N, Fonseca D, Fraenkel E, Gillery P, Giudici A, Jaisson S, Johansson M, Julve J, Lucas-Herald AK, Martinet W, Maurice P, McDonnell BJ, Ozbek EN, Pucci G, Pugh CJA, Rochfort KD, Roks AJM, Rotllan N, Shadiow J, Sohrabi Y, Spronck B, Szeri F, Terentes-Printzios D, Tunc Aydin E, Tura-Ceide O, Ucar E, Yetik-Anacak G. Pharmacological modulation of vascular ageing: A review from VascAgeNet. Ageing Res Rev 2023; 92:102122. [PMID: 37956927 DOI: 10.1016/j.arr.2023.102122] [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: 07/05/2023] [Revised: 10/27/2023] [Accepted: 11/09/2023] [Indexed: 11/20/2023]
Abstract
Vascular ageing, characterized by structural and functional changes in blood vessels of which arterial stiffness and endothelial dysfunction are key components, is associated with increased risk of cardiovascular and other age-related diseases. As the global population continues to age, understanding the underlying mechanisms and developing effective therapeutic interventions to mitigate vascular ageing becomes crucial for improving cardiovascular health outcomes. Therefore, this review provides an overview of the current knowledge on pharmacological modulation of vascular ageing, highlighting key strategies and promising therapeutic targets. Several molecular pathways have been identified as central players in vascular ageing, including oxidative stress and inflammation, the renin-angiotensin-aldosterone system, cellular senescence, macroautophagy, extracellular matrix remodelling, calcification, and gasotransmitter-related signalling. Pharmacological and dietary interventions targeting these pathways have shown potential in ameliorating age-related vascular changes. Nevertheless, the development and application of drugs targeting vascular ageing is complicated by various inherent challenges and limitations, such as certain preclinical methodological considerations, interactions with exercise training and sex/gender-related differences, which should be taken into account. Overall, pharmacological modulation of endothelial dysfunction and arterial stiffness as hallmarks of vascular ageing, holds great promise for improving cardiovascular health in the ageing population. Nonetheless, further research is needed to fully elucidate the underlying mechanisms and optimize the efficacy and safety of these interventions for clinical translation.
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Affiliation(s)
- Lynn Roth
- Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium.
| | - Soner Dogan
- Department of Medical Biology, School of Medicine, Yeditepe University, Istanbul, Turkiye
| | - Bilge Guvenc Tuna
- Department of Biophysics, School of Medicine, Yeditepe University, Istanbul, Turkiye
| | - Tamas Aranyi
- Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary; Department of Molecular Biology, Semmelweis University, Budapest, Hungary
| | - Sonia Benitez
- CIBER de Diabetes y enfermedades Metabólicas asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain; Cardiovascular Biochemistry, Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain
| | - Maria Borrell-Pages
- Cardiovascular Program ICCC, Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain; Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBER-CV), Instituto de Salud Carlos III, Madrid, Spain
| | - Perinur Bozaykut
- Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkiye
| | - Guido R Y De Meyer
- Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium
| | - Laurent Duca
- UMR CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Team 2 "Matrix Aging and Vascular Remodelling", Université de Reims Champagne Ardenne (URCA), Reims, France
| | - Nergiz Durmus
- Department of Pharmacology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkiye
| | - Diogo Fonseca
- Laboratory of Pharmacology and Pharmaceutical Care, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal; Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| | - Emil Fraenkel
- 1st Department of Internal Medicine, University Hospital, Pavol Jozef Šafárik University of Košice, Košice, Slovakia
| | - Philippe Gillery
- UMR CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Team 2 "Matrix Aging and Vascular Remodelling", Université de Reims Champagne Ardenne (URCA), Reims, France; Laboratoire de Biochimie-Pharmacologie-Toxicologie, Centre Hospitalier et Universitaire de Reims, Reims, France
| | - Alessandro Giudici
- Department of Biomedical Engineering, CARIM School for Cardiovascular Diseases, Maastricht University, the Netherlands; GROW School for Oncology and Reproduction, Maastricht University, the Netherlands
| | - Stéphane Jaisson
- UMR CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Team 2 "Matrix Aging and Vascular Remodelling", Université de Reims Champagne Ardenne (URCA), Reims, France; Laboratoire de Biochimie-Pharmacologie-Toxicologie, Centre Hospitalier et Universitaire de Reims, Reims, France
| | | | - Josep Julve
- CIBER de Diabetes y enfermedades Metabólicas asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain; Endocrinology, Diabetes and Nutrition group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain
| | | | - Wim Martinet
- Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium
| | - Pascal Maurice
- UMR CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Team 2 "Matrix Aging and Vascular Remodelling", Université de Reims Champagne Ardenne (URCA), Reims, France
| | - Barry J McDonnell
- Centre for Cardiovascular Health and Ageing, Cardiff Metropolitan University, Cardiff, UK
| | - Emine Nur Ozbek
- Department of Pharmacology, Faculty of Pharmacy, Ege University, Izmir, Turkiye
| | - Giacomo Pucci
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Christopher J A Pugh
- Centre for Cardiovascular Health and Ageing, Cardiff Metropolitan University, Cardiff, UK
| | - Keith D Rochfort
- School of Nursing, Psychotherapy, and Community Health, Dublin City University, Dublin, Ireland
| | - Anton J M Roks
- Department of Internal Medicine, Division of Vascular Disease and Pharmacology, Erasmus Medical Center, Erasmus University, Rotterdam, the Netherlands
| | - Noemi Rotllan
- CIBER de Diabetes y enfermedades Metabólicas asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain; Pathophysiology of lipid-related diseases, Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain
| | - James Shadiow
- School of Kinesiology, University of Michigan, Ann Arbor, MI, USA
| | - Yahya Sohrabi
- Molecular Cardiology, Dept. of Cardiology I - Coronary and Peripheral Vascular Disease, University Hospital Münster, Westfälische Wilhelms-Universität, 48149 Münster, Germany; Department of Medical Genetics, Third Faculty of Medicine, Charles University, 100 00 Prague, Czechia
| | - Bart Spronck
- Department of Biomedical Engineering, CARIM School for Cardiovascular Diseases, Maastricht University, the Netherlands; Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Australia
| | - Flora Szeri
- Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary
| | - Dimitrios Terentes-Printzios
- First Department of Cardiology, Hippokration Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Elif Tunc Aydin
- Department of Cardiology, Hospital of Ataturk Training and Research Hospital, Katip Celebi University, Izmir, Turkiye
| | - Olga Tura-Ceide
- Biomedical Research Institute-IDIBGI, Girona, Spain; Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Respiratorias, Madrid, Spain
| | - Eda Ucar
- Department of Biophysics, School of Medicine, Yeditepe University, Istanbul, Turkiye
| | - Gunay Yetik-Anacak
- Department of Pharmacology, Faculty of Pharmacy, Ege University, Izmir, Turkiye; Department of Pharmacology, Faculty of Pharmacy, Acıbadem Mehmet Aydinlar University, Istanbul, Turkiye.
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Parisi F, Fenizia C, Introini A, Zavatta A, Scaccabarozzi C, Biasin M, Savasi V. The pathophysiological role of estrogens in the initial stages of pregnancy: molecular mechanisms and clinical implications for pregnancy outcome from the periconceptional period to end of the first trimester. Hum Reprod Update 2023; 29:699-720. [PMID: 37353909 PMCID: PMC10628507 DOI: 10.1093/humupd/dmad016] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 05/12/2023] [Indexed: 06/25/2023] Open
Abstract
BACKGROUND Estrogens regulate disparate female physiological processes, thus ensuring reproduction. Altered estrogen levels and signaling have been associated with increased risks of pregnancy failure and complications, including hypertensive disorders and low birthweight babies. However, the role of estrogens in the periconceptional period and early pregnancy is still understudied. OBJECTIVE AND RATIONALE This review aims to summarize the current evidence on the role of maternal estrogens during the periconceptional period and the first trimester of pregnancies conceived naturally and following ART. Detailed molecular mechanisms and related clinical impacts are extensively described. SEARCH METHODS Data for this narrative review were independently identified by seven researchers on Pubmed and Embase databases. The following keywords were selected: 'estrogens' OR 'estrogen level(s)' OR 'serum estradiol' OR 'estradiol/estrogen concentration', AND 'early pregnancy' OR 'first trimester of pregnancy' OR 'preconceptional period' OR 'ART' OR 'In Vitro Fertilization (IVF)' OR 'Embryo Transfer' OR 'Frozen Embryo Transfer' OR 'oocyte donation' OR 'egg donation' OR 'miscarriage' OR 'pregnancy outcome' OR 'endometrium'. OUTCOMES During the periconceptional period (defined here as the critical time window starting 1 month before conception), estrogens play a crucial role in endometrial receptivity, through the activation of paracrine/autocrine signaling. A derailed estrogenic milieu within this period seems to be detrimental both in natural and ART-conceived pregnancies. Low estrogen levels are associated with non-conception cycles in natural pregnancies. On the other hand, excessive supraphysiologic estrogen concentrations at time of the LH peak correlate with lower live birth rates and higher risks of pregnancy complications. In early pregnancy, estrogen plays a massive role in placentation mainly by modulating angiogenic factor expression-and in the development of an immune-tolerant uterine micro-environment by remodeling the function of uterine natural killer and T-helper cells. Lower estrogen levels are thought to trigger abnormal placentation in naturally conceived pregnancies, whereas an estrogen excess seems to worsen pregnancy development and outcomes. WIDER IMPLICATIONS Most current evidence available endorses a relation between periconceptional and first trimester estrogen levels and pregnancy outcomes, further depicting an optimal concentration range to optimize pregnancy success. However, how estrogens co-operate with other factors in order to maintain a fine balance between local tolerance towards the developing fetus and immune responses to pathogens remains elusive. Further studies are highly warranted, also aiming to identify the determinants of estrogen response and biomarkers for personalized estrogen administration regimens in ART.
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Affiliation(s)
- F Parisi
- Department of Woman, Mother and Neonate, ‘V. Buzzi’ Children Hospital, ASST Fatebenefratelli Sacco, Milan, via L. Castelvetro 32, Milan, Italy
| | - C Fenizia
- Department of Pathophysiology and Transplantation, University of Milan, Milan, via F. Sforza 35, Milan 20122, Italy
- Department of Biomedical and Clinical Sciences, “L.Sacco” Hospital, University of Milan, Milan, via G.B. Grassi 74, Milan 20157, Italy
| | - A Introini
- Division of Infectious Diseases, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Nobels väg 5, Stockholm, Sweden
| | - A Zavatta
- Department of Woman, Mother and Neonate, ‘V. Buzzi’ Children Hospital, ASST Fatebenefratelli Sacco, Milan, via L. Castelvetro 32, Milan, Italy
| | - C Scaccabarozzi
- Department of Biomedical and Clinical Sciences, “L.Sacco” Hospital, University of Milan, Milan, via G.B. Grassi 74, Milan 20157, Italy
| | - M Biasin
- Department of Biomedical and Clinical Sciences, “L.Sacco” Hospital, University of Milan, Milan, via G.B. Grassi 74, Milan 20157, Italy
| | - V Savasi
- Department of Biomedical and Clinical Sciences, “L.Sacco” Hospital, University of Milan, Milan, via G.B. Grassi 74, Milan 20157, Italy
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Hsieh YC, Kao TC, Yang IJ, Yang PK, Chao KH, Chen MJ, Yang JH, Chen SU. Association between estradiol levels in early pregnancy and risk of preeclampsia after frozen embryo transfer. Front Endocrinol (Lausanne) 2023; 14:1223181. [PMID: 37795369 PMCID: PMC10545838 DOI: 10.3389/fendo.2023.1223181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 08/21/2023] [Indexed: 10/06/2023] Open
Abstract
Introduction The failure of remodeling the spiral arteries is associated with the pathogenesis of preeclampsia. Estradiol (E2) plays a crucial role in placentation and may be involved in the development of preeclampsia. However, there is a lack of data in this area. This study aims to assess the association between serum estradiol levels in early pregnancy and the risk of preeclampsia. Methods We conducted a retrospective cohort study on patients who conceived after frozen embryo transfer (FET) using data from a database at a university-affiliated in vitro fertilization center. The study period spanned from January 1, 2010, to December 31, 2020. Multivariable logistic regression analyses were performed to determine the adjusted effect of E2 levels on the risk of preeclampsia. We compared the odds ratios of preeclampsia across quartiles of E2 levels and assessed their significance. Results Serum E2 levels at the fifth gestational week were significantly different between women with and without preeclampsia after FET programmed cycles (607.5 ± 245.4 vs. 545.6 ± 294.4 pg/ml, p=0.009). A multivariable logistic regression model demonstrated that E2 levels in early pregnancy were independent risk factors for preeclampsia. We observed an increased odds ratio of preeclampsia with increasing quartiles of estradiol levels after adjusting for potential confounders in FET programmed cycles. When comparing quartiles 3 and 4 (E2 > 493 pg/ml at the fifth gestational week) to quartiles 1 and 2, the odds ratios of preeclampsia were significantly higher. Conclusion We found that serum E2 levels in early pregnancy may impact the risk of preeclampsia, particularly following FET programmed cycles. The association between E2 levels in early pregnancy and preeclampsia deserves further investigation.
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Affiliation(s)
- Yun-Chiao Hsieh
- Department of Obstetrics and Gynecology, National Taiwan University Hospital, Hsinchu, Taiwan
| | - Tzu-Ching Kao
- Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan
| | - Ih-Jane Yang
- Department of Obstetrics and Gynecology, National Taiwan University Hospital, Yunlin, Taiwan
| | - Po-Kai Yang
- Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan
| | - Kuang-Han Chao
- Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan
| | - Mei-Jou Chen
- Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan
- Livia Shangyu Wan Chair Professor of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Jehn-Hsiahn Yang
- Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan
| | - Shee-Uan Chen
- Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan
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Mechanism Underlying Naringenin Hypocholesterolemic Effects: Involvement of Estrogen Receptor α Subtype. Int J Mol Sci 2022; 23:ijms232415809. [PMID: 36555447 PMCID: PMC9779308 DOI: 10.3390/ijms232415809] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 12/08/2022] [Accepted: 12/10/2022] [Indexed: 12/15/2022] Open
Abstract
Naringenin (Nar) is one of major citrus flavonoids predominantly found in grapefruit and orange. In vivo studies have demonstrated Nar potential as a normolipidemic agent capable to reduce circulating cholesterol in hypercholesterolemic rabbits, rats, and patients, suggesting a new role for this molecule in cardiovascular disease prevention. Although Nar cholesterol-lowering effects are known, the underlying mechanisms have not yet been elucidated. Interestingly, Nar binds to the estrogen receptors (ERs), modulating both transcriptional and membrane-initiating signals. Although estrogen and ERs are deeply involved in lipid metabolism, no data are available regarding a putative role of these nuclear receptors as mediators of the hypocholesterolemic effect exerted by Nar. Thus, the aim of this work was to study the involvement of ERs in Nar-induced modulation of cholesterol metabolism. Results obtained in HepG2 cell line demonstrate that Nar can modulate the molecular network of cholesterol homeostasis. However, these effects were only partially dependent on the activity of estrogen receptor α. As a whole, our data highlight new molecular mechanisms by which Nar influences cholesterol metabolism, opening a new scenery about dietary impact on human health.
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Soleymani M, Masoudkabir F, Shabani M, Vasheghani-Farahani A, Behnoush AH, Khalaji A. Updates on Pharmacologic Management of Microvascular Angina. Cardiovasc Ther 2022; 2022:6080258. [PMID: 36382021 PMCID: PMC9626221 DOI: 10.1155/2022/6080258] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 08/29/2022] [Accepted: 10/17/2022] [Indexed: 01/14/2024] Open
Abstract
Microvascular angina (MVA), historically called cardiac syndrome X, refers to angina with nonobstructive coronary artery disease. This female-predominant cardiovascular disorder adds considerable health-related costs due to repeated diagnostic angiography and frequent hospital admissions. Despite the high prevalence of this diagnosis in patients undergoing coronary angiography, it is still a therapeutic challenge for cardiologists. Unlike obstructive coronary artery disease, with multiple evidence-based therapies and management guidelines, little is known regarding the management of MVA. During the last decade, many therapeutic interventions have been suggested for the treatment of MVA. However, there is a lack of summarization tab and update of current knowledge about pharmacologic management of MVA, mostly due to unclear pathophysiology. In this article, we have reviewed the underlying mechanisms of MVA and the outcomes of various medications in patients with this disease. Contrary to vasospastic angina in which normal angiogram is observed as well, nitrates are not effective in the treatment of MVA. Beta-blockers and calcium channel blockers have the strongest evidence of improving the symptoms. Moreover, the use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, statins, estrogen, and novel antianginal drugs has had promising outcomes. Investigations are still ongoing for vitamin D, omega-3, incretins, and n-acetyl cysteine, which have resulted in beneficial initial outcomes. We believe that the employment of the available results and results of the future large-scale trials into cardiac care guidelines would help reduce the global cost of cardiac care tremendously.
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Affiliation(s)
- Mosayeb Soleymani
- Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Farzad Masoudkabir
- Cardiac Primary Prevention Research Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
- Department of Cardiac Electrophysiology, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahsima Shabani
- Division of Cardiology, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Ali Vasheghani-Farahani
- Cardiac Primary Prevention Research Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
- Department of Cardiac Electrophysiology, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Hossein Behnoush
- Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
- Cardiac Primary Prevention Research Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Amirmohammad Khalaji
- Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
- Cardiac Primary Prevention Research Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
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de Paula LJC, Uchida AH, Rezende PC, Soares P, Scudeler TL. Protective or Inhibitory Effect of Pharmacological Therapy on Cardiac Ischemic Preconditioning: A Literature Review. Curr Vasc Pharmacol 2022; 20:409-428. [PMID: 35986546 DOI: 10.2174/1570161120666220819163025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 05/23/2022] [Accepted: 05/31/2022] [Indexed: 01/25/2023]
Abstract
Ischemic preconditioning (IP) is an innate phenomenon, triggered by brief, non-lethal cycles of ischemia/reperfusion applied to a tissue or organ that confers tolerance to a subsequent more prolonged ischemic event. Once started, it can reduce the severity of myocardial ischemia associated with some clinical situations, such as percutaneous coronary intervention (PCI) and intermittent aortic clamping during coronary artery bypass graft surgery (CABG). Although the mechanisms underlying IP have not been completely elucidated, several studies have shown that this phenomenon involves the participation of cell triggers, intracellular signaling pathways, and end-effectors. Understanding this mechanism enables the development of preconditioning mimetic agents. It is known that a range of medications that activate the signaling cascades at different cellular levels can interfere with both the stimulation and the blockade of IP. Investigations of signaling pathways underlying ischemic conditioning have identified a number of therapeutic targets for pharmacological manipulation. This review aims to present and discuss the effects of several medications on myocardial IP.
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Affiliation(s)
| | | | - Paulo Cury Rezende
- Instituto do Coração (InCor), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Paulo Soares
- Instituto do Coração (InCor), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Thiago Luis Scudeler
- Instituto do Coração (InCor), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
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Abstract
Peripartum cardiomyopathy (PPCM) is a potentially fatal form of idiopathic heart failure with variable prevalence across different countries and ethnic groups. The cause of PPCM is unclear, but environmental and genetic factors and pregnancy-associated conditions such as pre-eclampsia can contribute to the development of PPCM. Furthermore, animal studies have shown that impaired vascular and metabolic function might be central to the development of PPCM. A better understanding of the pathogenic mechanisms involved in the development of PPCM is necessary to establish new therapies that can improve the outcomes of patients with PPCM. Pregnancy hormones tightly regulate a plethora of maternal adaptive responses, including haemodynamic, structural and metabolic changes in the cardiovascular system. In patients with PPCM, the peripartum period is associated with profound and rapid hormonal fluctuations that result in a brief period of disrupted cardiovascular (metabolic) homeostasis prone to secondary perturbations. In this Review, we discuss the latest studies on the potential pathophysiological mechanisms of and risk factors for PPCM, with a focus on maternal cardiovascular changes associated with pregnancy. We provide an updated framework to further our understanding of PPCM pathogenesis, which might lead to an improvement in disease definition.
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Acconcia F, Fiocchetti M, Busonero C, Fernandez VS, Montalesi E, Cipolletti M, Pallottini V, Marino M. The extra-nuclear interactome of the estrogen receptors: implications for physiological functions. Mol Cell Endocrinol 2021; 538:111452. [PMID: 34500041 DOI: 10.1016/j.mce.2021.111452] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 08/19/2021] [Accepted: 09/02/2021] [Indexed: 02/07/2023]
Abstract
Over the last decades, a great body of evidence has defined a novel view of the cellular mechanism of action of the steroid hormone 17β-estradiol (E2) through its estrogen receptors (i.e., ERα and ERβ). It is now clear that the E2-activated ERs work both as transcription factors and extra-nuclear plasma membrane-localized receptors. The activation of a plethora of signal transduction cascades follows the E2-dependent engagement of plasma membrane-localized ERs and is required for the coordination of gene expression, which ultimately controls the occurrence of the pleiotropic effects of E2. The definition of the molecular mechanisms by which the ERs locate at the cell surface (i.e., palmitoylation and protein association) determined the quest for understanding the specificity of the extra-nuclear E2 signaling. The use of mice models lacking the plasma membrane ERα localization unveiled that the extra-nuclear E2 signaling is operational in vivo but tissue-specific. However, the underlying molecular details for such ERs signaling diversity in the perspective of the E2 physiological functions in the different cellular contexts are still not understood. Therefore, to gain insights into the tissue specificity of the extra-nuclear E2 signaling to physiological functions, here we reviewed the known ERs extra-nuclear interactors and tried to extrapolate from available databases the ERα and ERβ extra-nuclear interactomes. Based on literature data, it is possible to conclude that by specifically binding to extra-nuclear localized proteins in different sub-cellular compartments, the ERs fine-tune their molecular activities. Moreover, we report that the context-dependent diversity of the ERs-mediated extra-nuclear E2 actions can be ascribed to the great flexibility of the physical structures of ERs and the spatial-temporal organization of the logistics of the cells (i.e., the endocytic compartments). Finally, we provide lists of proteins belonging to the potential ERα and ERβ extra-nuclear interactomes and propose that the systematic experimental definition of the ERs extra-nuclear interactomes in different tissues represents the next step for the research in the ERs field. Such characterization will be fundamental for the identification of novel druggable targets for the innovative treatment of ERs-related diseases.
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Affiliation(s)
- Filippo Acconcia
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy.
| | - Marco Fiocchetti
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy
| | - Claudia Busonero
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy
| | - Virginia Solar Fernandez
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy
| | - Emiliano Montalesi
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy
| | - Manuela Cipolletti
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy
| | - Valentina Pallottini
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy
| | - Maria Marino
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy.
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Paolini C, Mugnai G, Dalla Valle C, Volpiana A, Ferraglia A, Frigo AC, Bilato C. Effects and clinical implications of sacubitril/valsartan on left ventricular reverse remodeling in patients affected by chronic heart failure: A 24-month follow-up. IJC HEART & VASCULATURE 2021; 35:100821. [PMID: 34179333 PMCID: PMC8213880 DOI: 10.1016/j.ijcha.2021.100821] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 05/10/2021] [Accepted: 06/03/2021] [Indexed: 12/11/2022]
Abstract
Background Compared to angiotensin inhibition, angiotensin-neprilysin "blockade" improves mortality and reduces hospitalizations in patients with heart failure (HF) with reduced ejection fraction (EF). Sacubitril/valsartan is known to influence left ventricular (LV) reverse remodeling with systolic function improvement, although underlying mechanisms remain partially unclear. Our objectives were to evaluate whether sacubitril/valsartan promotes LV remodeling and improves LV ejection fraction (LVEF) (above the 35% threshold by echocardiographic evaluation) and to identify predictors of reverse remodeling in a real-world setting. Methods New York Heart Association (NYHA) class II-III patients with EF ≤ 35% were consecutively enrolled. All patients were on optimal medical therapy on the initiation of sacubitril/valsartan therapy. Full clinical and multi-parametric echocardiographic evaluation, electrocardiogram, and laboratory tests were performed at baseline and after 3, 6, 12, and 24 months. Results In total, 69 patients were recruited from July 2016 to August 2018. Reverse remodeling was observed in 57.7% (30/52) of patients, occurring within 3, 6, 12, and 24 months in 2, 11, 13, and 4 patients, respectively. Twenty-four (46%) patients showed LVEF improvement above the threshold of 35% during follow-up, occurring in 1, 10, 9, and 4 patients within 3, 6, 12, and 24 months, respectively. Primitive dilated cardiomyopathy and female gender were identified as significant predictors of reverse remodeling. NYHA class was improved in both remodeling and non-remodeling patients. Conclusion Sacubitril/valsartan promotes favorable cardiac remodeling and significantly improves LVEF in a significant proportion of HF patients within 24 months, both in NYHA class II and III patients with HF.
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Key Words
- ACEi, Angiotensin-converting enzyme inhibitors
- ARBs, Angiotensin II receptor blockers
- ARNI, Angiotensin receptor-neprilysin inhibitor
- CI, Confidence interval
- CRT, Cardiac resynchronization therapy
- ESC, European Society of Cardiology
- GFR, Glomerular filtration rate
- HF, Heart failure
- HFrEF, Heart failure with reduced ejection fraction
- Heart failure
- ICD, Implantable cardioverter-defibrillator
- LA, Left atrium
- LV, Left ventricular
- LVEF, Left ventricular ejection fraction
- MR, Mitral regurgitation
- NYHA, New York Heart Association
- OMT, Optimal medical therapy
- OR, Odds ratio
- RAAS, Renin-angiotensin-aldosterone system
- Reverse remodeling
- Sacubitril/valsartan
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Affiliation(s)
- Carla Paolini
- Division of Cardiology, West Vicenza General Hospitals, Arzignano-Vicenza, Italy
| | - Giacomo Mugnai
- Division of Cardiology, West Vicenza General Hospitals, Arzignano-Vicenza, Italy
| | - Chiara Dalla Valle
- Division of Cardiology, West Vicenza General Hospitals, Arzignano-Vicenza, Italy
| | - Andrea Volpiana
- Division of Cardiology, West Vicenza General Hospitals, Arzignano-Vicenza, Italy
| | - Alessandra Ferraglia
- Division of Cardiology, West Vicenza General Hospitals, Arzignano-Vicenza, Italy
| | - Anna Chiara Frigo
- Biostatistics, Epidemiology and Public Health Unit, Department of Cardiac, Thoracic and Vascular Sciences, University of Padova, Padova, Italy
| | - Claudio Bilato
- Division of Cardiology, West Vicenza General Hospitals, Arzignano-Vicenza, Italy
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10
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Liang XX, Wang RY, Guo YZ, Cheng Z, Lv DY, Luo MH, He A, Luo SX, Xia Y. Phosphorylation of Akt at Thr308 regulates p-eNOS Ser1177 during physiological conditions. FEBS Open Bio 2021; 11:1953-1964. [PMID: 33993653 PMCID: PMC8255840 DOI: 10.1002/2211-5463.13194] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 04/28/2021] [Accepted: 05/12/2021] [Indexed: 11/30/2022] Open
Abstract
Endothelial nitric oxide synthase (eNOS)‐derived nitric oxide (NO) plays a crucial role in maintaining vascular homeostasis. As a hallmark of eNOS activation, phosphorylation of eNOS at Ser1177 induced by activated protein kinase B (PKB/Akt) is pivotal for NO production. The complete activation of Akt requires its phosphorylation of both Thr308 and Ser473. However, which site plays the main role in regulating phosphorylation of eNOS Ser1177 is still controversial. The purpose of the present study is to explore the specific regulatory mechanism of phosphorylated Akt in eNOS activation. Inhibition of Akt Thr308 phosphorylation by a specific inhibitor or by siRNA in vitro led to a decrease in eNOS phosphorylation at Ser1177 and to lower NO concentration in the cell culture medium of HUVECs. However, inhibiting p‐Akt Ser473 had no effect on eNOS phosphorylation at Ser1177. Next, we administered mice with inhibitors to downregulate p‐Akt Ser473 or Thr308 activity. Along with the inhibition of p‐Akt Thr308, vascular p‐eNOS Ser1177 protein was simultaneously downregulated in parallel with a decrease in plasma NO concentration. Additionally, we cultured HUVECs at various temperature conditions (37, 22, and 4 °C). The results showed that p‐Akt Ser473 was gradually decreased in line with the reduction in temperature, accompanied by increased levels of p‐Akt Thr308 and p‐eNOS Ser1177. Taken together, our study indicates that the phosphorylation of Akt at Thr308, but not at Ser473, plays a more significant role in regulating p‐eNOS Ser1177 levels under physiological conditions.
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Affiliation(s)
- Xiao-Xue Liang
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, China.,Institute of Life Science, Chongqing Medical University, China
| | - Rui-Yu Wang
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, China.,Institute of Life Science, Chongqing Medical University, China
| | - Yong-Zheng Guo
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, China.,Institute of Life Science, Chongqing Medical University, China
| | - Zhe Cheng
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, China.,Institute of Life Science, Chongqing Medical University, China
| | - Ding-Yi Lv
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, China.,Institute of Life Science, Chongqing Medical University, China
| | - Ming-Hao Luo
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, China.,Institute of Life Science, Chongqing Medical University, China
| | - An He
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, China.,Institute of Life Science, Chongqing Medical University, China
| | - Su-Xin Luo
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, China
| | - Yong Xia
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, China.,Institute of Life Science, Chongqing Medical University, China
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Camal Ruggieri IN, Cícero AM, Issa JPM, Feldman S. Bone fracture healing: perspectives according to molecular basis. J Bone Miner Metab 2021; 39:311-331. [PMID: 33151416 DOI: 10.1007/s00774-020-01168-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 10/13/2020] [Indexed: 12/11/2022]
Abstract
Fractures have a great impact on health all around the world and with fracture healing optimization; this problem could be resolved partially. To make a practical contribution to this issue, the knowledge of bone tissue, cellularity, and metabolism is essential, especially cytoskeletal architecture and its transformations according to external pressures. Special physical and chemical characteristics of the extracellular matrix (ECM) allow the transmission of mechanical stimuli from outside the cell to the plasmatic membrane. The osteocyte cytoskeleton is conformed by a complex network of actin and microtubules combined with crosslinker proteins like vinculin and fimbrin, connecting and transmitting outside stimuli through EMC to cytoplasm. Herein, critical signaling pathways like Cx43-depending ones, MAPK/ERK, Wnt, YAP/TAZ, Rho-ROCK, and others are activated due to mechanical stimuli, resulting in osteocyte cytoskeletal changes and ECM remodeling, altering the tissue and, therefore, the bone. In recent years, the osteocyte has gained more interest and value in relation to bone homeostasis as a great coordinator of other cell populations, thanks to its unique functions. By integrating the latest advances in relation to intracellular signaling pathways, mechanotransmission system of the osteocyte and bone tissue engineering, there are promising experimental strategies, while some are ready for clinical trials. This work aims to show clearly and precisely the integration between cytoskeleton and main molecular pathways in relation to mechanotransmission mechanism in osteocytes, and the use of this theoretical knowledge in therapeutic tools for bone fracture healing.
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Affiliation(s)
- Iván Nadir Camal Ruggieri
- School of Medicine, LABOATEM (Osteoarticular Biology, Tissue Engineering and Emerging Therapies Laboratory), Biological Chemistry Cat, School of Medicine, Rosario National University, Rosario, Argentina.
| | - Andrés Mauricio Cícero
- School of Medicine, LABOATEM (Osteoarticular Biology, Tissue Engineering and Emerging Therapies Laboratory), Biological Chemistry Cat, School of Medicine, Rosario National University, Rosario, Argentina
| | | | - Sara Feldman
- School of Medicine, LABOATEM (Osteoarticular Biology, Tissue Engineering and Emerging Therapies Laboratory), Biological Chemistry Cat, School of Medicine, Rosario National University, Rosario, Argentina
- Research Council of the Rosario National University (CIUNR) and CONICET, Rosario, Argentina
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12
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Pooja, Sharma V, Sharma M, Varshney R, Kumar B, Sethy NK. Association Between 17β-Estradiol Receptors and Nitric Oxide Signaling Augments High-Altitude Adaptation of Ladakhi Highlanders. High Alt Med Biol 2021; 22:174-183. [PMID: 33602001 DOI: 10.1089/ham.2020.0187] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Pooja, Vandana Sharma, Manish Sharma, Rajeev Varshney, Bhuvnesh Kumar, and Niroj Kumar Sethy. Association between 17β-estradiol receptors and nitric oxide signaling augments high-altitude adaptation of Ladakhi highlanders. High Alt Med Biol. 22: 174-183, 2021. Background: Genomic studies have identified positive natural selection of plasma membrane estrogen receptor signaling pathway for Himalayan highlanders. We sought to investigate significance of this pathway for high-altitude adaptation by studying Ladakhi highlanders. Materials and Methods: We recruited 25 healthy Ladakhi males (age range: 19-37, height: 164 ± 6 cm, and weight 59 ± 4 kg) at Leh (altitude 3,520 m) and age matched sea level volunteers at Delhi (altitude 215 m), India. We evaluated circulatory levels of 17β-estradiol (E2) and testosterone (T) and levels of E2 biosynthesis pathway proteins. In addition, we analyzed mRNA levels of E2 pathway genes and their association with nitric oxide (NO) availability. Results: We observed higher circulatory E2 and lower testosterone (T) in Ladakhi highlanders compared to lowlanders. Studying E2 pathway genes, we identified higher transcript levels of E2 receptors ESR1 (2.02-fold) and ESR2 (3.87-fold) in Ladakhi highlanders. Higher NOS3 mRNA, plasma level of endothelial NO synthase (eNOS), p-eNOS Ser1177, NOx (nitrate and nitrite), and cGMP were observed for Ladakhi highlanders. In addition, we observed a positive correlation between E2 with plasma NOx (r = 0.52, p = 0.002) and cGMP (r = 0.72, p = 0.007) for Ladakhi highlanders. Conclusion: Our results demonstrate higher circulatory E2 and lower T levels in Ladakhi highlanders. Higher levels of E2 and its receptors (ESR1 and ESR2) are positively associated with observed higher levels of eNOS signaling pathway metabolites. These results highlight the functional importance of E2 and its receptors for Himalayan pattern of high-altitude adaptation.
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Affiliation(s)
- Pooja
- Peptide and Proteomics Division, Defence Institute of Physiology and Allied Sciences (DIPAS), Defence Research and Development Organization (DRDO), Delhi, India
| | - Vandana Sharma
- Peptide and Proteomics Division, Defence Institute of Physiology and Allied Sciences (DIPAS), Defence Research and Development Organization (DRDO), Delhi, India
| | - Manish Sharma
- Peptide and Proteomics Division, Defence Institute of Physiology and Allied Sciences (DIPAS), Defence Research and Development Organization (DRDO), Delhi, India
| | - Rajeev Varshney
- Peptide and Proteomics Division, Defence Institute of Physiology and Allied Sciences (DIPAS), Defence Research and Development Organization (DRDO), Delhi, India
| | - Bhuvnesh Kumar
- Peptide and Proteomics Division, Defence Institute of Physiology and Allied Sciences (DIPAS), Defence Research and Development Organization (DRDO), Delhi, India
| | - Niroj Kumar Sethy
- Peptide and Proteomics Division, Defence Institute of Physiology and Allied Sciences (DIPAS), Defence Research and Development Organization (DRDO), Delhi, India
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13
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Zhou L, Poon CCW, Wong KY, Cao S, Dong X, Zhang Y, Wong MS. Icariin ameliorates estrogen-deficiency induced bone loss by enhancing IGF-I signaling via its crosstalk with non-genomic ERα signaling. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2021; 82:153413. [PMID: 33339654 DOI: 10.1016/j.phymed.2020.153413] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 10/20/2020] [Accepted: 11/09/2020] [Indexed: 06/12/2023]
Abstract
BACKGROUND Rapid, non-genomic estrogen receptor (ER) signaling plays an integral role in mediating the tissue selective properties of ER modulators. Icariin, a bone bioactive flavonoid, has been reported to selectively activate non-genomic ERα signaling in in vitro and in vivo studies. PURPOSE The mechanisms underlying the estrogen-like bone protective effects of icariin are not fully understood, especially those that are related to insulin-like growth factor I (IGF-1) signaling. The bone protective effects of icariin were investigated in female mature ovariectomized (OVX) rats and the signaling of IGF-IR- ERα cross-talk was determined in osteoblastic cells. STUDY DESIGN AND METHODS Icariin at 3 different dosages (50, 500 and 3000 ppm) were orally administrated to rats for 3 months through daily intake of phytoestrogen-free animal diets containing icariin. Bone marrow stromal cells (BMSCs) and osteoclast precursors from femurs were harvested for experiments and RNA-sequencing. The interactions between IGF-IR and non-genomic ERα signaling were examined in pre-osteoblastic MC3T3-E1 cells and mature osteoblasts differentiated from BMSCs. RESULTS Our results show that chronic administration of icariin to OVX rats significantly protected them against bone loss at the long bone and lumbar spine without inducing any uterotrophic effects. Ex vivo studies using BMSCs and osteoclast precursors confirmed the stimulatory effects of icariin on osteoblastogenesis and its inhibitory effects on osteoclastogenesis, respectively. RNA-sequencing analysis of mRNA from BMSCs revealed that icariin at 500 ppm significantly altered IGF-1 signaling as well as PI3K-Akt pathways. Our results demonstrated for the first time the rapid induction of interactions between IGF-IR and ERα as well as IGF-IR signaling and the downstream Akt phosphorylation by icariin in MC3T3-E1 cells. The activation of ERα and Akt phosphorylation by icariin in MC3T3-E1 cells and the osteogenic effects of icariin on ALP activity in mature osteoblasts were shown to be IGF-IR-dependent. CONCLUSION Our findings reveal that icariin activates both ERα and Akt via enhancing rapid induction of IGF-1 signaling in osteoblastic cells for osteogenesis and might be regarded as a novel pathway-selective phytoestrogen for management of postmenopausal osteoporosis.
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Affiliation(s)
- Liping Zhou
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR
| | - Christina Chui-Wa Poon
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR
| | - Ka-Ying Wong
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR
| | - Sisi Cao
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR
| | - Xiaoli Dong
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR
| | - Yan Zhang
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR; Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, PR China.
| | - Man-Sau Wong
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR; State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, PR China.
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14
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Liu J, Song G, Meng T, Zhao G. Identification of Differentially Expressed Genes and Signaling Pathways in Placenta Tissue of Early-Onset and Late-Onset Pre-Eclamptic Pregnancies by Integrated Bioinformatics Analysis. Med Sci Monit 2020; 26:e921997. [PMID: 32497025 PMCID: PMC7294845 DOI: 10.12659/msm.921997] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Background Pre-eclampsia (PE) can be divided into 2 sub-groups: early-onset and late-onset PE. Although these sub-groups show overlapping molecular and cellular mechanisms and similar clinical manifestations, they are regarded as 2 different phenotypes with heterogeneous manifestations. The pathophysiological mechanisms underlying early-onset and late-onset PE still remain unclear. Therefore, the present study aimed to identify the key genes and pathways related to early-onset and late-onset PE, and to investigate the molecular mechanisms that are involved in gene regulation. Material/Methods Our analysis involved the Gene Expression Series (GSE) 74341 and GSE22526 from the National Center of Biotechnology Information (NCBI) Gene Expression Omnibus Database. These 2 microarray datasets included 15 patients with early-onset PE and 15 patients with late-onset PE. Results Our analyses identified 15 differentially expressed genes (DEGs), including CGA, EGR1, HBB, HBA2, LEP, and LHB. Gene Ontology (GO) functional annotation showed that the biological functions of these DEGs were mainly associated with steroid biosynthetic, oxidative stress, angiogenesis, and sex differentiation. Signaling pathway analyses showed that these DEGs were mainly involved in the prolactin signaling pathway, hormone metabolism, the AMPK signaling pathway, and the FoxO signaling pathway. Protein-protein interaction (PPI) network analysis identified 4 genes with the highest degree of interaction. The hub genes for this selection of DEGS were EGR1, LEP, and HBB. Conclusions Integrated bioinformatic analyses provide us with a new approach to further understand the pathophysiology and molecular mechanisms underlying early-onset and late-onset PE. The DEGs identified in this study represent potential biomarkers for the early diagnosis of PE and may provide significant options the treatment of these 2 subtypes of PE.
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Affiliation(s)
- Jing Liu
- Department of Obstetrics, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China (mainland)
| | - Guang Song
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China (mainland)
| | - Tao Meng
- Department of Obstetrics, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China (mainland)
| | - Ge Zhao
- Department of Obstetrics, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China (mainland)
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15
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Mandalà M. Influence of Estrogens on Uterine Vascular Adaptation in Normal and Preeclamptic Pregnancies. Int J Mol Sci 2020; 21:ijms21072592. [PMID: 32276444 PMCID: PMC7177259 DOI: 10.3390/ijms21072592] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 04/02/2020] [Accepted: 04/03/2020] [Indexed: 12/20/2022] Open
Abstract
During pregnancy, the maternal cardiovascular system undergoes significant changes, including increased heart rate, cardiac output, plasma volume, and uteroplacental blood flow (UPBF) that are required for a successful pregnancy outcome. The increased UPBF is secondary to profound circumferential growth that extends from the downstream small spiral arteries to the upstream conduit main uterine artery. Although some of the mechanisms underlying uterine vascular remodeling are, in part, known, the factors that drive the remodeling are less clear. That higher circulating levels of estrogens are positively correlated with gestational uterine vascular remodeling suggests their involvement in this process. Estrogens binding to the estrogen receptors expressed in cytotrophoblast cells and in the uterine artery wall stimulate an outward hypertrophic remodeling of uterine vasculature. In preeclampsia, generally lower concentrations of estrogens limit the proper uterine remodeling, thereby reducing UPBF increases and restricting the growth of the fetus. This review aims to report estrogenic regulation of the maternal uterine circulatory adaptation in physiological and pathological pregnancy that favors vasodilation, and to consider the underlying molecular mechanisms by which estrogens regulate uteroplacental hemodynamics.
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Affiliation(s)
- Maurizio Mandalà
- Department of Biology, Ecology and Earth Sciences, University of Calabria, 87036 Rende, Italy
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16
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Fernandes ES, Celani MFS, Fistarol M, Geber S. Effectiveness of the short-term use of Cimicifuga racemosa in the endothelial function of postmenopausal women: a double-blind, randomized, controlled trial. Climacteric 2019; 23:245-251. [PMID: 31691621 DOI: 10.1080/13697137.2019.1682542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Objective: This study aimed to assess the effects of daily use of Cimicifuga racemosa on endothelial function through flow-mediated dilation of the brachial artery, when used for 28 days by healthy postmenopausal women.Methods: The double-blind, randomized, placebo-controlled study included two groups of postmenopausal women (n = 31 each). The subjects were clinically assessed and flow-mediated dilation of the brachial artery was measured before and after 28 days of treatment. Patients received dry extract corresponding to 160 mg C. racemosa (extract with 4 mg of triterpene glycosides) or placebo.Results: Mean age, time since menopause, and body mass index in the two groups were similar. The measurements of flow-mediated dilation of the brachial artery, pre and post treatment, respectively, showed a significant increase in patients who used C. racemosa (p = 0.006), unlike patients who used placebo, who did not present changes in the outcome of flow-mediated dilation of the brachial artery after 28 days of use (p ≥ 0.05). When comparing the number of women in both groups who showed an increase in flow-mediated dilation, a significant difference was found in the measurements of the treated group after the use of the medication (p = 0.018).Conclusions: Daily use of 160 mg C. racemosa extract by postmenopausal women for 28 days beneficially influences endothelial function by promoting elasticity of the brachial artery.
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Affiliation(s)
- E S Fernandes
- Department of Obstetrics and Gynecology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - M F S Celani
- Department of Obstetrics and Gynecology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - M Fistarol
- Department of Obstetrics and Gynecology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - S Geber
- Department of Obstetrics and Gynecology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
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Horie K, Nanashima N, Maeda H. Phytoestrogenic Effects of Blackcurrant Anthocyanins Increased Endothelial Nitric Oxide Synthase (eNOS) Expression in Human Endothelial Cells and Ovariectomized Rats. Molecules 2019; 24:molecules24071259. [PMID: 30935162 PMCID: PMC6480453 DOI: 10.3390/molecules24071259] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Revised: 03/19/2019] [Accepted: 03/22/2019] [Indexed: 01/08/2023] Open
Abstract
Phytoestrogens are plant-derived chemicals that are found in many foods and have estrogenic activity. We previously showed that blackcurrant extract (BCE) and anthocyanins have phytoestrogenic activity mediated via estrogen receptors (ERs), and anthocyanins may improve vascular function. BCE contains high levels of anthocyanins, but their health-promoting effects are unclear. This study examined the effects of BCE on the regulation of endothelial nitric oxide synthase (eNOS) expression and nitric oxide (NO) synthesis in human endothelial cells as key regulators in cardiovascular disease. The results showed that eNOS mRNA levels were significantly upregulated in BCE- or anthocyanin-treated human vascular endothelial cells but decreased in cells treated with fulvestrant, an ER antagonist. These results corresponded with NO levels, suggesting that BCE and anthocyanin may regulate NO synthesis via eNOS expression. Thus, the phytoestrogenic effects exerted by BCE via ERs influenced eNOS mRNA expression and NO synthesis. In vivo, we investigated whether anthocyanin-rich BCE upregulated eNOS protein expression in ovariectomized (OVX) rats, a widely used animal model of menopause. Our results showed that anthocyanin-rich BCE significantly upregulated eNOS mRNA levels and NO synthesis through phytoestrogenic activity and therefore promoted blood vessel health in OVX rats as a postmenopausal model.
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Affiliation(s)
- Kayo Horie
- Department of Bioscience and Laboratory Medicine, Hirosaki University Graduate School of Health Sciences, 66-1 Hon-cho, Hirosaki, Aomori 036-8564, Japan.
| | - Naoki Nanashima
- Department of Bioscience and Laboratory Medicine, Hirosaki University Graduate School of Health Sciences, 66-1 Hon-cho, Hirosaki, Aomori 036-8564, Japan.
| | - Hayato Maeda
- Faculty of Agriculture and Life Science, Hirosaki University, 3 Bunkyo-cho, Hirosaki, Aomori 036-8561, Japan.
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18
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Berkane N, Liere P, Oudinet JP, Hertig A, Lefèvre G, Pluchino N, Schumacher M, Chabbert-Buffet N. From Pregnancy to Preeclampsia: A Key Role for Estrogens. Endocr Rev 2017; 38:123-144. [PMID: 28323944 DOI: 10.1210/er.2016-1065] [Citation(s) in RCA: 131] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Accepted: 02/28/2017] [Indexed: 02/08/2023]
Abstract
Preeclampsia (PE) results in placental dysfunction and is one of the primary causes of maternal and fetal mortality and morbidity. During pregnancy, estrogen is produced primarily in the placenta by conversion of androgen precursors originating from maternal and fetal adrenal glands. These processes lead to increased plasma estrogen concentrations compared with levels in nonpregnant women. Aberrant production of estrogens could play a key role in PE symptoms because they are exclusively produced by the placenta and they promote angiogenesis and vasodilation. Previous assessments of estrogen synthesis during PE yielded conflicting results, possibly because of the lack of specificity of the assays. However, with the introduction of reliable analytical protocols using liquid chromatography/mass spectrometry or gas chromatography/mass spectrometry, more recent studies suggest a marked decrease in estradiol levels in PE. The aim of this review is to summarize current knowledge of estrogen synthesis, regulation in the placenta, and biological effects during pregnancy and PE. Moreover, this review highlights the links among the occurrence of PE, estrogen biosynthesis, angiogenic factors, and cardiovascular risk factors. A close link between estrogen dysregulation and PE occurrence might validate estrogen levels as a biomarker but could also reveal a potential approach for prevention or cure of PE.
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Affiliation(s)
- Nadia Berkane
- Department of Gynecology and Obstetrics of University Hospital of Geneva, 1205, Genève, Switzerland.,U1195, INSERM and University Paris Sud, 94276 Kremlin Bicêtre, France
| | - Philippe Liere
- U1195, INSERM and University Paris Sud, 94276 Kremlin Bicêtre, France
| | - Jean-Paul Oudinet
- U1195, INSERM and University Paris Sud, 94276 Kremlin Bicêtre, France
| | - Alexandre Hertig
- Department of Nephrology, Tenon Hospital, APHP, 75020 Paris, France.,University of Pierre and Marie Curie, Sorbonne University, Paris 06, 75005 Paris, France.,Unité Mixte de Recherche Scientifique 1155, F-75020 Paris, France
| | - Guillaume Lefèvre
- University of Pierre and Marie Curie, Sorbonne University, Paris 06, 75005 Paris, France.,Department of Biochemistry and Hormonology, Tenon Hospital, APHP, F-75020 Paris, France
| | - Nicola Pluchino
- Department of Gynecology and Obstetrics of University Hospital of Geneva, 1205, Genève, Switzerland
| | | | - Nathalie Chabbert-Buffet
- University of Pierre and Marie Curie, Sorbonne University, Paris 06, 75005 Paris, France.,Department of Obstetrics, Gynecology and Reproductive Medicine, Tenon Hospital, APHP, F-75020 Paris, France.,INSERM, UMR-S938, Centre de Recherche Saint-Antoine, F-75012 Paris, France
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Barton M. Not lost in translation: Emerging clinical importance of the G protein-coupled estrogen receptor GPER. Steroids 2016; 111:37-45. [PMID: 26921679 DOI: 10.1016/j.steroids.2016.02.016] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2016] [Revised: 02/13/2016] [Accepted: 02/22/2016] [Indexed: 01/21/2023]
Abstract
It has been 20years that the G protein-coupled estrogen receptor (GPER) was cloned as the orphan receptor GPR30 from multiple cellular sources, including vascular endothelial cells. Here, I will provide an overview of estrogen biology and the historical background leading to the discovery of rapid vascular estrogen signaling. I will also review the recent advances in the understanding of the mechanisms underlying GPER function, its role in physiology and disease, some of the currently available GPER-targeting drugs approved for clinical use such as SERMs (selective estrogen receptor modulators) and SERDs (selective estrogen receptor downregulators). Many of currently used drugs such as tamoxifen, raloxifene, or faslodex™/fulvestrant were discovered targeting GPER many years after they had been introduced to the clinics for entirely different purposes. This has important implications for the clinical use of these drugs and their modes of action, which I have termed 'reverse translational medicine'. In addition, environmental pollutants known as 'endocrine disruptors' have been found to bind to GPER. This article also discusses recent evidence in these areas as well as opportunities in translational clinical medicine and GPER research, including medical genetics, personalized medicine, prevention, and its theranostic use.
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Affiliation(s)
- Matthias Barton
- Molecular Internal Medicine, University of Zürich, Switzerland.
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Maekawa H, Serrone JC, Tjahjadi M, Hernesniemi J. RETRACTED ARTICLE: The role of estrogen on the pathology of cerebral aneurysms. Expert Rev Neurother 2016; 16:927-35. [DOI: 10.1080/14737175.2016.1189827] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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21
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Zhu J, Song W, Li L, Fan X. Endothelial nitric oxide synthase: a potential therapeutic target for cerebrovascular diseases. Mol Brain 2016; 9:30. [PMID: 27000187 PMCID: PMC4802712 DOI: 10.1186/s13041-016-0211-9] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Accepted: 03/12/2016] [Indexed: 12/15/2022] Open
Abstract
Endothelial nitric oxide (NO) is a significant signaling molecule that regulates cerebral blood flow (CBF), playing a pivotal role in the prevention and treatment of cerebrovascular diseases. However, achieving the expected therapeutic efficacy is difficult using direct administration of NO donors. Therefore, endothelial nitric oxide synthase (eNOS) becomes a potential therapeutic target for cerebrovascular diseases. This review summarizes the current evidence supporting the importance of CBF to cerebrovascular function, and the roles of NO and eNOS in CBF regulation.
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Affiliation(s)
- Jinqiang Zhu
- State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, P. R. China.,Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 312 Anshanxi Road, Nankai District, Tianjin, 300193, P. R. China
| | - Wanshan Song
- Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300150, P. R. China
| | - Lin Li
- State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, P. R. China.,Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 312 Anshanxi Road, Nankai District, Tianjin, 300193, P. R. China
| | - Xiang Fan
- State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, P. R. China. .,Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 312 Anshanxi Road, Nankai District, Tianjin, 300193, P. R. China.
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Sathish V, Prakash Y. Sex Differences in Pulmonary Anatomy and Physiology. SEX DIFFERENCES IN PHYSIOLOGY 2016:89-103. [DOI: 10.1016/b978-0-12-802388-4.00006-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
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23
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Li X, Cai C, Luo R, Jiang R, Zeng J, Tang Y, Chen Y, Fu M, He T, Hua W. The usefulness of age and sex to predict all-cause mortality in patients with dilated cardiomyopathy: a single-center cohort study. Clin Interv Aging 2015; 10:1479-86. [PMID: 26396507 PMCID: PMC4577275 DOI: 10.2147/cia.s88565] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Objective Recent studies have shown that sex and age are associated with outcomes in patients with cardiomyopathy. The purpose of this study was to determine the all-cause mortality of dilated cardiomyopathy (DCM) by age and sex. Methods and results The patients were divided into non-elderly (age <60 years, n=811) and elderly (age ≥60 years, n=331) groups. No difference in the all-cause mortality rate was observed between elderly and non-elderly patients (27.2% vs 22.2%, log-rank χ2=2.604, P=0.107). Furthermore, no significant difference in mortality was observed between the male and female patients (23.3% vs 24.5%, log-rank χ2=0.707, P=0.400). However, subgroup analysis revealed that elderly male patients exhibited a higher mortality rate than non-elderly male patients (29.4% vs 21.3%, log-rank χ2=5.898, P=0.015), while no difference was observed between the elderly female patients and non-elderly female patients. In the Cox analysis, neither age nor sex was a significant independent predictor of all-cause mortality in patients with DCM. Conclusion In conclusion, no significant difference in mortality between male and female patients or between the elderly and non-elderly patients was observed. Only among males was a difference in mortality observed; elderly male patients experienced greater mortality than that of non-elderly male patients. No effect of age or sex on all-cause mortality was observed in patients with DCM.
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Affiliation(s)
- Xiaoping Li
- Department of Cardiology, Hospital of the University of Electronic Science and Technology of China, Sichuan Provincial People's Hospital, Chengdu, Sichuan, People's Republic of China ; School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, People's Republic of China ; Department of Clinical Electrophysiology, Fuwai Hospital and Cardiovascular Institute, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People's Republic of China
| | - Chi Cai
- Department of Clinical Electrophysiology, Fuwai Hospital and Cardiovascular Institute, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People's Republic of China
| | - Rong Luo
- Key Laboratory of Thermoregulation and Inflammation of Sichuan Higher Education Institutes, Chengdu Medical College, Chengdu, Sichuan, People's Republic of China
| | - Rongjian Jiang
- Department of Cardiology, Hospital of the University of Electronic Science and Technology of China, Sichuan Provincial People's Hospital, Chengdu, Sichuan, People's Republic of China
| | - Jie Zeng
- Department of Cardiology, Hospital of the University of Electronic Science and Technology of China, Sichuan Provincial People's Hospital, Chengdu, Sichuan, People's Republic of China
| | - Yijia Tang
- Department of Cardiology, Hospital of the University of Electronic Science and Technology of China, Sichuan Provincial People's Hospital, Chengdu, Sichuan, People's Republic of China
| | - Yang Chen
- Department of Cardiology, Hospital of the University of Electronic Science and Technology of China, Sichuan Provincial People's Hospital, Chengdu, Sichuan, People's Republic of China
| | - Michael Fu
- Department of Medicine, Sahlgrenska University Hospital/Östra Hospital, Gothenburg, Sweden
| | - Tao He
- Department of Cardiology, Hospital of the University of Electronic Science and Technology of China, Sichuan Provincial People's Hospital, Chengdu, Sichuan, People's Republic of China
| | - Wei Hua
- Department of Clinical Electrophysiology, Fuwai Hospital and Cardiovascular Institute, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People's Republic of China
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Montt-Guevara MM, Giretti MS, Russo E, Giannini A, Mannella P, Genazzani AR, Genazzani AD, Simoncini T. Estetrol Modulates Endothelial Nitric Oxide Synthesis in Human Endothelial Cells. Front Endocrinol (Lausanne) 2015; 6:111. [PMID: 26257704 PMCID: PMC4510430 DOI: 10.3389/fendo.2015.00111] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Accepted: 07/06/2015] [Indexed: 01/27/2023] Open
Abstract
Estetrol (E4) is a natural human estrogen that is present at high concentrations during pregnancy. E4 has been reported to act as an endogenous estrogen receptor modulator, exerting estrogenic actions on the endometrium or the central nervous system but presenting antagonistic effects on the breast. Due to these characteristics, E4 is currently being developed for a number of clinical applications, including contraception and menopausal hormone therapy. Endothelial nitric oxide (NO) is a key player for vascular function and disease during pregnancy and throughout aging in women. Endothelial NO is an established target of estrogens that enhance its formation in human endothelial cells. We here addressed the effects of E4 on the activity and expression of the endothelial nitric oxide synthase (eNOS) in cultured human umbilical vein endothelial cells (HUVEC). E4 stimulated the activation of eNOS and NO secretion in HUVEC. E4 was significantly less effective compared to E2, and a peculiar concentration-dependent effect was found, with higher amounts of E4 being less effective than lower concentrations. When E2 was combined with E4, an interesting pattern was noted. E4 antagonized NO synthesis induced by pregnancy-like E2 concentrations. However, E4 did not impede the modest induction of NO synthesis associated with postmenopausal-like E2 levels. These results support the hypothesis that E4 may be a regulator of NO synthesis in endothelial cells and raise questions on its peculiar signaling in this context. Our results may be useful to interpret the role of E4 during human pregnancy and possibly to help develop this interesting steroid for clinical use.
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Affiliation(s)
- Maria Magdalena Montt-Guevara
- Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Maria Silvia Giretti
- Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Eleonora Russo
- Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Andrea Giannini
- Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Paolo Mannella
- Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Andrea Riccardo Genazzani
- Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | | | - Tommaso Simoncini
- Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
- *Correspondence: Tommaso Simoncini, Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Clinical and Experimental Medicine, Division of Obstetrics and Gynecology, University of Pisa, Via Roma 57, Pisa 56100, Italy,
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25
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Han G, White RE. G-protein-coupled estrogen receptor as a new therapeutic target for treating coronary artery disease. World J Cardiol 2014; 6:367-375. [PMID: 24976908 PMCID: PMC4072826 DOI: 10.4330/wjc.v6.i6.367] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2013] [Revised: 03/06/2014] [Accepted: 04/29/2014] [Indexed: 02/06/2023] Open
Abstract
Coronary heart disease (CHD) continues to be the greatest mortality risk factor in the developed world. Estrogens are recognized to have great therapeutic potential to treat CHD and other cardiovascular diseases; however, a significant array of potentially debilitating side effects continues to limit their use. Moreover, recent clinical trials have indicated that long-term postmenopausal estrogen therapy may actually be detrimental to cardiovascular health. An exciting new development is the finding that the more recently discovered G-protein-coupled estrogen receptor (GPER) is expressed in coronary arteries-both in coronary endothelium and in smooth muscle within the vascular wall. Accumulating evidence indicates that GPER activation dilates coronary arteries and can also inhibit the proliferation and migration of coronary smooth muscle cells. Thus, selective GPER activation has the potential to increase coronary blood flow and possibly limit the debilitating consequences of coronary atherosclerotic disease. This review will highlight what is currently known regarding the impact of GPER activation on coronary arteries and the potential signaling mechanisms stimulated by GPER agonists in these vessels. A thorough understanding of GPER function in coronary arteries may promote the development of new therapies that would help alleviate CHD, while limiting the potentially dangerous side effects of estrogen therapy.
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26
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Akman L, Duygu H, Akercan F, Ulukus M, Ozerkan F, Akin M. The effects of different hormone treatment on endothelial function in healthy postmenopausal women. Gynecol Endocrinol 2013; 29:867-72. [PMID: 23875965 DOI: 10.3109/09513590.2013.813471] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
We aimed to compare the effects of different types of hormone treatment (HT) on endothelial function by means of brachial artery ultrasonographic examination in postmenopausal women. Sixty-two healthy postmenopausal women were included in this study. Subjects were assigned to one of the five groups receiving 6 months of treatment [estrogen (conjugated estrogen), estrogen (conjugated estrogen) plus progesterone (medroxyprogesterone acetate; MPA), raloxifene, tibolone or control]. Endothelial function was assessed by measurement of flow-mediated dilatation (FMD) and nitrate-dependent dilatation in the brachial artery. At the end of 6 months, FMD values were found to be significantly increased in women with HT use than the control group (p = 0.001). In subgroups, FMD increased significantly in the estrogen [12 ± 7 versus 25 ± 8, p = 0.001] and raloxifene groups [7 ± 5 versus 11 ± 3, p < 0.01] compared to tibolone and estrogen plus progesterone groups. In conclusion, endothelial function is impaired in postmenopausal women. Both estrogen and raloxifene regimens may improve endothelial functions in healthy postmenopausal women. The direct protective effects of these HT on the healthy endothelium may be more remarkable than the favorable effects on lipid profile.
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Affiliation(s)
- Levent Akman
- Ege University Faculty of Medicine, Department of Obstetrics and Gynecology, Bornova 35100, İzmir, Turkey.
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VandeVrede L, Abdelhamid R, Qin Z, Choi J, Piyankarage S, Luo J, Larson J, Bennett BM, Thatcher GRJ. An NO donor approach to neuroprotective and procognitive estrogen therapy overcomes loss of NO synthase function and potentially thrombotic risk. PLoS One 2013; 8:e70740. [PMID: 23976955 PMCID: PMC3745399 DOI: 10.1371/journal.pone.0070740] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2013] [Accepted: 06/28/2013] [Indexed: 01/16/2023] Open
Abstract
Selective estrogen receptor modulators (SERMs) are effective therapeutics that preserve favorable actions of estrogens on bone and act as antiestrogens in breast tissue, decreasing the risk of vertebral fractures and breast cancer, but their potential in neuroprotective and procognitive therapy is limited by: 1) an increased lifetime risk of thrombotic events; and 2) an attenuated response to estrogens with age, sometimes linked to endothelial nitric oxide synthase (eNOS) dysfunction. Herein, three 3(rd) generation SERMs with similar high affinity for estrogen receptors (ERα, ERβ) were studied: desmethylarzoxifene (DMA), FDMA, and a novel NO-donating SERM (NO-DMA). Neuroprotection was studied in primary rat neurons exposed to oxygen glucose deprivation; reversal of cholinergic cognitive deficit was studied in mice in a behavioral model of memory; long term potentiation (LTP), underlying cognition, was measured in hippocampal slices from older 3×Tg Alzheimer's transgenic mice; vasodilation was measured in rat aortic strips; and anticoagulant activity was compared. Pharmacologic blockade of GPR30 and NOS; denudation of endothelium; measurement of NO; and genetic knockout of eNOS were used to probe mechanism. Comparison of the three chemical probes indicates key roles for GPR30 and eNOS in mediating therapeutic activity. Procognitive, vasodilator and anticoagulant activities of DMA were found to be eNOS dependent, while neuroprotection and restoration of LTP were both shown to be dependent upon GPR30, a G-protein coupled receptor mediating estrogenic function. Finally, the observation that an NO-SERM shows enhanced vasodilation and anticoagulant activity, while retaining the positive attributes of SERMs even in the presence of NOS dysfunction, indicates a potential therapeutic approach without the increased risk of thrombotic events.
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Affiliation(s)
- Lawren VandeVrede
- Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Ramy Abdelhamid
- Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Zhihui Qin
- Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Jaewoo Choi
- Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Sujeewa Piyankarage
- Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Jia Luo
- Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - John Larson
- Department of Psychiatry, Neuropsychiatric Institute, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Brian M. Bennett
- Department of Biomedical and Molecular Sciences, Faculty of Health Sciences, Queen's University, Kingston, Ontario, Canada
| | - Gregory R. J. Thatcher
- Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, United States of America
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Effects of raloxifene on cognition, mental health, sleep and sexual function in menopausal women: A systematic review of randomized controlled trials. Maturitas 2013; 75:341-8. [DOI: 10.1016/j.maturitas.2013.05.010] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2013] [Revised: 05/13/2013] [Accepted: 05/15/2013] [Indexed: 01/25/2023]
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Abstract
Sex differences in the incidence of liver cirrhosis and portal hypertension have been reported by epidemiological studies. Previous studies have indicated that estrogen therapy improved hepatic fibrosis, inhibited the activation of hepatic stellate cells, and reduced portal pressure, whereas the administration of exogenous estrogens resulted in some potential risks, limiting their clinical use. However, the biological actions of estrogens are mediated by three subtypes of estrogen receptors (ERs): ERα, ERβ, and G-protein-coupled ER. These ER subtypes act in distinct ways and exert different biological effects that mediate genomic and nongenomic events, resulting in tissue-specific responses. In addition, active estrogen metabolites, with little or no affinity for ERs, could mediate the fibrosuppressive effect of estrogens through an ER-independent pathway. Taken together, such specific estrogen derivatives as ER selective agonists, or active estrogen metabolites, would provide novel therapeutic opportunities, stratifying this hormonal treatment, thereby reducing undesired side-effects in the treatment of liver cirrhosis and portal hypertension.
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30
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Maclaran K, Stevenson JC. Primary Prevention of Cardiovascular Disease with HRT. WOMENS HEALTH 2012; 8:63-74. [DOI: 10.2217/whe.11.87] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Prevention of cardiovascular disease has increasingly important health implications as our population ages. Menopause is associated with the development of cardiovascular risk factors and there are many plausible biological mechanisms through which estrogen may confer cardiovascular protection. Despite a wealth of observational data to support the use of estrogen, large randomized controlled trials failed to demonstrate a benefit. It is now becoming clearer that the beneficial cardiovascular effects of estrogen are greatest in younger women and those closest to menopause. This has led to the development of the timing hypothesis. Use of age-appropriate estrogen doses is crucial to maximize cardiovascular benefits while minimizing risk of adverse effects such as venous thromboembolism and stroke.
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Affiliation(s)
| | - John C Stevenson
- Imperial College London, London, UK
- Nations Heart & Lung Institute, Royal Brompton Hospital, Sydney Street, London, SW3 6NP, UK
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Meyer MR, Prossnitz ER, Barton M. GPER/GPR30 and Regulation of Vascular Tone and Blood Pressure. ACTA ACUST UNITED AC 2011; 11:255-261. [PMID: 24999376 DOI: 10.2174/1871522211108040255] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Natural estrogens such as 17β-estradiol are endogenous vasodilators and have been implicated in the gender differences of hypertension. These hormones activate estrogen receptors ERα and ERβ, which mediate part of estrogen-dependent vasodilation. In addition, a novel G protein-coupled estrogen-binding receptor termed GPER/GPR30 has been identified that is expressed in the cardiovascular system. Using knock-out animals or drugs selectively targeting GPER/GPR30, a significant role for this receptor as a mediator of acute estrogen-dependent vasodilation involving nitric oxide (NO) and blood pressure-lowering activity has been demonstrated. The accumulating evidence that GPER/GPR30 is responsible for control of vascular tone indicates that this receptor may represent a novel drug target for pharmacologic treatment of hypertension in postmenopausal women and possibly also men.
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Affiliation(s)
- Matthias R Meyer
- Molecular Internal Medicine, University of Zurich, Zurich, Switzerland ; Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States
| | - Eric R Prossnitz
- Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States
| | - Matthias Barton
- Molecular Internal Medicine, University of Zurich, Zurich, Switzerland
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Regitz-Zagrosek V, Seeland U. Sex and gender differences in myocardial hypertrophy and heart failure. Wien Med Wochenschr 2011; 161:109-16. [PMID: 21461800 DOI: 10.1007/s10354-011-0892-8] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2010] [Accepted: 02/22/2011] [Indexed: 11/29/2022]
Abstract
Cardiovascular disease is the most common cause of death in men and women worldwide. Men develop most, but not all, cardiovascular diseases at an earlier age while the number of affected women significantly increases with higher age. Heart failure (HF) is a common cause of cardiovascular death and carries a poor prognosis in both genders. Risk factors and myocardial adaptations in HF in men and women are different. Female hearts develop a more favorable physiological form of myocardial remodeling than male hearts. This may be related to sex hormones, estrogens and testosterone. A clinical study for gender differences in human aortic stenosis supports the hypotheses. HF management differs between both sexes, with underdiagnosis and undertreatment and less use of invasive therapies in women. Nevertheless, women frequently have better outcomes than men. Gender research will contribute directly to patient-oriented benefit by suggesting clinical protocols.
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Affiliation(s)
- Vera Regitz-Zagrosek
- Institute of Gender in Medicine (GiM) and Center for Cardiovascular Research, Charité University Medicine, Berlin, Germany.
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Meyer MR, Prossnitz ER, Barton M. The G protein-coupled estrogen receptor GPER/GPR30 as a regulator of cardiovascular function. Vascul Pharmacol 2011; 55:17-25. [PMID: 21742056 PMCID: PMC3216677 DOI: 10.1016/j.vph.2011.06.003] [Citation(s) in RCA: 121] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2011] [Revised: 06/19/2011] [Accepted: 06/25/2011] [Indexed: 12/29/2022]
Abstract
Endogenous estrogens are important regulators of cardiovascular homeostasis in premenopausal women and delay the development of hypertension and coronary artery disease. These hormones act via three different estrogen receptors affecting both gene transcription and rapid signaling pathways in a complex interplay. In addition to the classical estrogen receptors ERα and ERβ, which are known mediators of estrogen-dependent vascular effects, a G protein-coupled estrogen receptor termed GPER that is expressed in the cardiovascular system has recently been identified. Endogenous human 17β-estradiol, selective estrogen receptor modulators (SERMs) including tamoxifen and raloxifene, and selective estrogen receptor downregulators (SERDs) such as ICI 182,780 are all agonists of GPER, which has been implicated in the regulation of vasomotor tone and protection from myocardial ischemia/reperfusion injury. As a result, understanding the individual role of ERα, ERβ, and GPER in cardiovascular function has become increasingly complex. With accumulating evidence that GPER is responsible for a variety of beneficial cardiovascular effects of estrogens, this receptor may represent a novel target to develop effective strategies for the treatment of cardiovascular diseases by tissue-specific, selective activation of estrogen-dependent molecular pathways devoid of side effects seen with conventional hormone therapy.
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Affiliation(s)
- Matthias R. Meyer
- Molecular Internal Medicine, University of Zurich, Zurich, Switzerland
- Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States
| | - Eric R. Prossnitz
- Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States
| | - Matthias Barton
- Molecular Internal Medicine, University of Zurich, Zurich, Switzerland
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Abdelhamid R, Luo J, VandeVrede L, Kundu I, Michalsen B, Litosh VA, Schiefer IT, Gherezghiher T, Yao P, Qin Z, Thatcher GRJ. Benzothiophene Selective Estrogen Receptor Modulators Provide Neuroprotection by a novel GPR30-dependent Mechanism. ACS Chem Neurosci 2011; 2:256-268. [PMID: 21731800 PMCID: PMC3124785 DOI: 10.1021/cn100106a] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2010] [Accepted: 02/24/2011] [Indexed: 12/18/2022] Open
Abstract
The clinical benzothiophene SERM (BT-SERM), raloxifene, was compared with estrogens in protection of primary rat neurons against oxygen-glucose deprivation (OGD). Structure-activity relationships for neuroprotection were determined for a family of BT-SERMs displaying a spectrum of ERα and ERβ binding affinity and agonist/antagonist activity, leading to discovery of a neuroprotective pharmacophore, present in the clinically relevant SERMS, raloxifene and desmethylarzoxifene (DMA), for which submicromolar potency was observed for neuroprotection. BT-SERM neuroprotection did not correlate with binding to ER nor classical ER activity, however, both the neuroprotective SERMs and estrogens were shown, using pharmacological probes, to activate the same kinase signaling cascades. The antiestrogen ICI 182,780 inhibited the actions of estrogens, but not those of BT-SERMs, whereas antagonism of the G-protein coupled receptor, GPR30, was effective for both SERMs and estrogens. Since SERMs have antioxidant activity, ER-independent mechanisms were studied using the classical phenolic antioxidants, BHT and Trolox, and the Nrf2-dependent cytoprotective electrophile, sulforaphane. However, neuroprotection by these agents was not sensitive to GPR30 antagonism. Collectively, these data indicate that the activity of neuroprotective BT-SERMs is GPR30-dependent and ER-independent and not mediated by antioxidant effects. Comparison of novel BT-SERM derivatives and analogs identified a neuroprotective pharmacophore of potential use in design of novel neuroprotective agents with a spectrum of ER activity.
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Affiliation(s)
- Ramy Abdelhamid
- Department of Medicinal Chemistry and Pharmacognosy (M/C 781), College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231, United States
| | - Jia Luo
- Department of Medicinal Chemistry and Pharmacognosy (M/C 781), College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231, United States
| | - Lawren VandeVrede
- Department of Medicinal Chemistry and Pharmacognosy (M/C 781), College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231, United States
| | - Indraneel Kundu
- Department of Medicinal Chemistry and Pharmacognosy (M/C 781), College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231, United States
| | - Bradley Michalsen
- Department of Medicinal Chemistry and Pharmacognosy (M/C 781), College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231, United States
| | - Vladislav A. Litosh
- Department of Medicinal Chemistry and Pharmacognosy (M/C 781), College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231, United States
| | - Isaac T. Schiefer
- Department of Medicinal Chemistry and Pharmacognosy (M/C 781), College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231, United States
| | - Teshome Gherezghiher
- Department of Medicinal Chemistry and Pharmacognosy (M/C 781), College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231, United States
| | - Ping Yao
- Department of Medicinal Chemistry and Pharmacognosy (M/C 781), College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231, United States
| | - Zhihui Qin
- Department of Medicinal Chemistry and Pharmacognosy (M/C 781), College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231, United States
| | - Gregory R. J. Thatcher
- Department of Medicinal Chemistry and Pharmacognosy (M/C 781), College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231, United States
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Shibata MA, Morimoto J, Shibata E, Kurose H, Akamatsu K, Li ZL, Kusakabe M, Ohmichi M, Otsuki Y. Raloxifene inhibits tumor growth and lymph node metastasis in a xenograft model of metastatic mammary cancer. BMC Cancer 2010; 10:566. [PMID: 20958960 PMCID: PMC2978204 DOI: 10.1186/1471-2407-10-566] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2010] [Accepted: 10/19/2010] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The effects of raloxifene, a novel selective estrogen receptor modulator, were studied in a mouse metastatic mammary cancer model expressing cytoplasmic ERα. METHODS Mammary tumors, induced by inoculation of syngeneic BALB/c mice with BJMC3879luc2 cells, were subsequently treated with raloxifene at 0, 18 and 27 mg/kg/day using mini-osmotic pumps. RESULTS In vitro study demonstrated that the ERα in BJMC3879luc2 cells was smaller (between 50 and 64 kDa) than the normal-sized ERα (66 kDa) and showed cytoplasmic localization. A statistically significant but weak estradiol response was observed in this cell line. When BJMC3879luc2 tumors were implanted into mice, the ERα mRNA levels were significantly higher in females than in males. In vitro studies showed that raloxifene induced mitochondria-mediated apoptosis and cell-cycle arrest in the G1-phase and a decrease in the cell population in the S-phase. In animal experiments, tumor volumes were significantly suppressed in the raloxifene-treated groups. The multiplicity of lymph node metastasis was significantly decreased in the 27 mg/kg group. Levels of apoptosis were significantly increased in the raloxifene-treated groups, whereas the levels of DNA synthesis were significantly decreased in these groups. No differences in microvessel density in tumors were observed between the control and raloxifene-treated groups. The numbers of dilated lymphatic vessels containing intraluminal tumor cells were significantly reduced in mammary tumors in the raloxifene-treated groups. The levels of ERα mRNA in mammary tumors tended to be decreased in the raloxifene-treated groups. CONCLUSION These results suggest that the antimetastatic activity of raloxifene in mammary cancer expressing cytoplasmic ERα may be a crucial finding with clinical applications and that raloxifene may be useful as an adjuvant therapy and for the chemoprevention of breast cancer development.
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Affiliation(s)
- Masa-Aki Shibata
- Department of Anatomy and Cell Biology, Division of Life Sciences, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan
| | - Junji Morimoto
- Laboratory Animal Center, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan
| | - Eiko Shibata
- Department of Anatomy and Cell Biology, Division of Life Sciences, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan
- Department of Bioscience, National Cardiovascular Center Research Institute, Suita, Osaka, Japan
| | - Hitomi Kurose
- Department of Anatomy and Cell Biology, Division of Life Sciences, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan
| | - Kanako Akamatsu
- Department of Systems Bioscience for Drug Discovery, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Zhong-Lian Li
- Department of Anatomy and Cell Biology, Division of Life Sciences, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan
| | - Moriaki Kusakabe
- Research Center for Food Safety, University of Tokyo Graduate School of Agricultural and Life Sciences, Tokyo, Japan
| | - Masahide Ohmichi
- Department of Gynecology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan
| | - Yoshinori Otsuki
- Department of Anatomy and Cell Biology, Division of Life Sciences, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan
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Ozbasar D, Toros U, Ozkaya O, Sezik M, Uzun H, Genc H, Kaya H. Raloxifene decreases serum malondialdehyde and nitric oxide levels in postmenopausal women with end-stage renal disease under chronic hemodialysis therapy. J Obstet Gynaecol Res 2010; 36:133-7. [DOI: 10.1111/j.1447-0756.2009.01086.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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Kim KH, Bender JR. Membrane-initiated actions of estrogen on the endothelium. Mol Cell Endocrinol 2009; 308:3-8. [PMID: 19549586 PMCID: PMC2701909 DOI: 10.1016/j.mce.2009.03.025] [Citation(s) in RCA: 89] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2008] [Revised: 03/27/2009] [Accepted: 03/30/2009] [Indexed: 12/31/2022]
Abstract
Estrogen-induced rapid, membrane-initiated activation of numerous signal transduction cascades has been shown in animal, cellular and molecular vascular studies, which support the favorable effects of estrogen on vascular structure and function. These effects are mediated by distinct forms of estrogen receptor (ER) alpha. This includes estrogen-stimulated, rapid activation of endothelial nitric oxide synthase (eNOS), resulting in elaboration of the athero-protective, angiogenesis-promoting product nitric oxide (NO). An N-terminus truncated short isoform of ERalpha, ER46, plays a critical role in membrane-initiated, rapid responses to 17beta-estradiol (E2) in human endothelial cells (ECs). We have proposed a ER46-centered, eNOS-activating molecular complex in human EC caveolar membranes, containing c-Src, phosphatidylinositol 3-kinase (PI3K), Akt and eNOS. In this review, we describe estrogen-induced, rapid, non-genomic actions in the endothelium.
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Affiliation(s)
| | - Jeffrey R. Bender
- Corresponding author: Jeffrey R. Bender, Division of Cardiovascular Medicine and Departments of Internal Medicine and Immunobiology, Yale University School of Medicine, 300 Cedar Street, New Haven, Connecticut 06520, USA. Tel. 203-737-2223; Fax. 203-785-7567; E-Mail:
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Mahmoodzadeh S, Fritschka S, Dworatzek E, Pham TH, Becher E, Kuehne A, Davidson MM, Regitz-Zagrosek V. Nuclear factor-kappaB regulates estrogen receptor-alpha transcription in the human heart. J Biol Chem 2009; 284:24705-14. [PMID: 19584059 DOI: 10.1074/jbc.m109.000463] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Estrogen receptor (ER)-mediated effects have been associated with the modulation of myocardial hypertrophy in animal models and in humans, but the regulation of ER expression in the human heart has not yet been analyzed. In various cell lines and tissues, multiple human estrogen receptor alpha (hERalpha) mRNA isoforms are transcribed from distinct promoters and differ in their 5'-untranslated regions. Using PCR-based strategies, we show that in the human heart the ERalpha mRNA is transcribed from multiple promoters, namely, A, B, C, and F, of which the F-promoter is most frequently used variant. Transient transfection reporter assays in a human cardiac myocyte cell line (AC16) with F-promoter deletion constructs demonstrated a negative regulatory region within this promoter. Site-directed mutagenesis and electrophoretic mobility shift assays indicated that NF-kappaB binds to this region. An inhibition of NF-kappaB activity by parthenolide significantly increased the transcriptional activity of the F-promoter. Increasing NF-kappaB expression by tumor necrosis factor-alpha reduced the expression of ERalpha, indicating that the NF-kappaB pathway inhibits expression of ERalpha in human cardiomyocytes. Finally, 17beta-estradiol induced the transcriptional activity of hERalpha promoters A, B, C, and F. In conclusion, inflammatory stimuli suppress hERalpha expression via activation and subsequent binding of NF-kappaB to the ERalpha F-promoter, and 17beta-estradiol/hERalpha may antagonize the inhibitory effect of NF-kappaB. This suggests interplay between estrogen/estrogen receptors and the pro-hypertrophic and inflammatory responses to NF-kappaB.
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Affiliation(s)
- Shokoufeh Mahmoodzadeh
- Institute of Gender in Medicine, Charité-Universitaetsmedizin Berlin, Berlin 10115, Germany.
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Collins P, Mosca L, Geiger MJ, Grady D, Kornitzer M, Amewou-Atisso MG, Effron MB, Dowsett SA, Barrett-Connor E, Wenger NK. Effects of the selective estrogen receptor modulator raloxifene on coronary outcomes in the Raloxifene Use for The Heart trial: results of subgroup analyses by age and other factors. Circulation 2009; 119:922-30. [PMID: 19204301 DOI: 10.1161/circulationaha.108.817577] [Citation(s) in RCA: 88] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND The Raloxifene Use for The Heart (RUTH) trial showed that raloxifene, a selective estrogen receptor modulator, had no overall effect on the incidence of coronary events in women with established coronary heart disease or coronary heart disease risk factors. We provide detailed results of the effect of raloxifene on coronary outcomes over time and for 24 subgroups (17 predefined, 7 post hoc). METHODS AND RESULTS Postmenopausal women (n=10 101; mean age, 67 years) were randomized to raloxifene 60 mg/d or placebo for a median of 5.6 years. Coronary outcomes were assessed by treatment group in women with coronary heart disease risk factors and those with established coronary heart disease. Raloxifene had no effect on the incidence of coronary events in any subgroup except in the case of a post hoc age subgroup analysis using age categories defined in the Women's Health Initiative randomized trials. The effect of raloxifene on the incidence of coronary events differed significantly by age (interaction P=0.0118). The incidence of coronary events in women <60 years of age was significantly lower in those assigned raloxifene (50 events) compared with placebo (84 events; hazard ratio, 0.59; 95% confidence interval, 0.41 to 0.83; P=0.003; absolute risk reduction, 36 per 1000 women treated for 1 year). No difference was found between treatment groups in the incidence of coronary events in women > or =60 and <70 or > or =70 years of age. CONCLUSIONS In postmenopausal women at increased risk of coronary events, the overall lack of benefit of raloxifene was similar across the prespecified subgroups.
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Affiliation(s)
- Peter Collins
- Department of Cardiology, Royal Brompton and Harefield NHS Trust and NHLI, Imperial College London, Sydney Street, London, UK.
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Arias-Loza PA, Jazbutyte V, Pelzer T. Genetic and pharmacologic strategies to determine the function of estrogen receptor alpha and estrogen receptor beta in cardiovascular system. ACTA ACUST UNITED AC 2008; 5 Suppl A:S34-45. [PMID: 18395682 DOI: 10.1016/j.genm.2008.03.005] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/21/2007] [Indexed: 12/15/2022]
Abstract
BACKGROUND The biological functions of estrogens extend beyond the female and male reproductive tract, affecting the cardiovascular and renal systems. Traditional views on the role of postmenopausal hormone therapy (HT) in protecting against heart disease, which were challenged by clinical end point studies that found adverse effects of combined HT, are now being replaced by more differentiated concepts suggesting a beneficial role of early and unopposed HT that does not include a progestin. OBJECTIVE We reviewed recent insights, concepts, and research results on the biology of both estrogen receptor (ER) subtypes, ERalpha and ERbeta, in cardiac and vascular tissues. Knowledge of these ER subtypes is crucial to understanding gender and estrogen effects and to developing novel, exciting strategies that may have a profound clinical impact. METHODS This review focuses on in vivo studies and includes data presented at the August 2007 meeting of the American Physiological Society as well as data from a search of the MEDLINE and Ovid databases from January 1986 to November 2007. Search results were restricted to English-language publications, using the following search terms: estrogen, estrogen receptor alpha, estrogen receptor beta, estrogen receptor alpha agonist, estrogen receptor alpha antagonist, estrogen receptor beta agonist, estrogen receptor beta antagonist, PPT, DPN, heart, vasculature, ERKO mice, BERKO mice, transgenic mice, and knockout mice. RESULTS Genetic mouse models and pharmacologic studies that employed selective as well as nonselective ER agonists support the concept that both ER subtypes confer protective effects in experimental models of human heart disease, including hypertension, cardiac hypertrophy, and chronic heart failure. CONCLUSIONS Genetic models and novel ligands hold the promise of further improving our understanding of estrogen action in multiple tissues and organs. These efforts will ultimately enhance the safety and efficacy of HT and may also result in new applications for synthetic female sex hormone analogues.
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Wong CM, Yung LM, Leung FP, Tsang SY, Au CL, Chen ZY, Yao X, Cheng CHK, Lau CW, Gollasch M, Huang Y. Raloxifene protects endothelial cell function against oxidative stress. Br J Pharmacol 2008; 155:326-34. [PMID: 18574454 DOI: 10.1038/bjp.2008.262] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND AND PURPOSE Maintaining a delicate balance between the generation of nitric oxide (NO) and removal of reactive oxygen species (ROS) within the vascular wall is crucial to the physiological regulation of vascular tone. Increased production of ROS reduces the effect and/or bioavailability of NO, leading to an impaired endothelial function. This study tested the hypothesis that raloxifene, a selective oestrogen receptor modulator, can prevent endothelial dysfunction under oxidative stress. EXPERIMENTAL APPROACH Changes in isometric tension were measured in rat aortic rings. The content of cyclic GMP in aortic tissue was determined by radioimmunoassay. Phosphorylation of endothelial NOS (eNOS) and Akt was assayed by Western blot analysis. KEY RESULTS In rings with endothelium, ACh-induced relaxations were attenuated by a ROS-generating reaction (hypoxanthine plus xanthine oxidase, HXXO). The impaired relaxations were ameliorated by acute treatment with raloxifene. HXXO suppressed the ACh-stimulated increase in cyclic GMP levels; this effect was antagonized by raloxifene. The improved endothelial function by raloxifene was abolished by ICI 182,780, and by wortmannin or LY294002. Raloxifene also protected endothelial cell function against H2O2. Raloxifene increased the phosphorylation of eNOS at Ser-1177 and Akt at Ser-473; this effect was blocked by ICI 182,780. Finally, raloxifene was not directly involved in scavenging ROS, and neither inhibited the activity of xanthine oxidase nor stimulated that of superoxide dismutase. CONCLUSION AND IMPLICATIONS Raloxifene is effective against oxidative stress-induced endothelial dysfunction in vitro through an ICI 182,780-sensitive mechanism that involves the increased phosphorylation and activity of Akt and eNOS in rat aortae.
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Affiliation(s)
- C M Wong
- Institute of Vascular Medicine and Department of Physiology, Chinese University of Hong Kong, Hong Kong, China
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Ullrich ND, Krust A, Collins P, MacLeod KT. Genomic deletion of estrogen receptors ERalpha and ERbeta does not alter estrogen-mediated inhibition of Ca2+ influx and contraction in murine cardiomyocytes. Am J Physiol Heart Circ Physiol 2008; 294:H2421-7. [PMID: 18441199 DOI: 10.1152/ajpheart.01225.2007] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Estrogens modify contraction of vascular smooth muscle and cardiomyocytes, but suggestions that they confer protective effects on the cardiovascular system remain controversial. The negative inotropic effects of estrogens are a consequence of L-type Ca2+ channel inhibition, but the underlying mechanisms remain elusive. We tested the hypothesis that membrane-associated estrogen receptors (ER)-alpha and -beta are involved. We measured the effect of estrogens on Ca2+ current (ICaL) in isolated ventricular cardiomyocytes of wild-type (WT), ERalpha knockout (ERalphaKO), and ERbetaKO mice using the whole cell patch-clamp technique at 37 degrees C. No differences in current densities or inactivation profiles of ICaL were found under control conditions in WT, ERalphaKO, and ERbetaKO cardiomyocytes, suggesting that absence of either ER has no effect on functional properties of ICaL. In all groups, application of raloxifene (2 microM) or 17alpha- or 17beta-estradiol (50 microM) reduced ICaL (P < 0.001). Raloxifene decreased ICaL by 44 +/- 9% (mean +/- SE) in WT (n = 5), 34 +/- 5% in ERalphaKO (n = 5), and 30 +/- 5% in ERbetaKO mice (n = 8). 17alpha-Estradiol reduced ICaL by 41 +/- 10% in WT (n = 4), 34 +/- 12% in ERalphaKO (n = 7), and 38 +/- 8% in ERbetaKO mice (n = 7). 17beta-Estradiol inhibited ICaL by 31 +/- 4% in WT (n = 4), 28 +/- 6% in ERalphaKO (n = 3), and 42 +/- 3% in ERbetaKO mice (n = 5). Decreases in cell shortening occurred in parallel with these findings. Our results suggest that inhibition of ICaL and the decrease in contraction by estrogens do not depend on ERalpha or ERbeta.
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Affiliation(s)
- Nina D Ullrich
- Imperial College London, Cardiac Medicine, National Heart and Lung Institute, London, United Kingdom
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Ho KJ, Liao JK. Non-nuclear actions of estrogen: new targets for prevention and treatment of cardiovascular disease. Mol Interv 2008; 2:219-28. [PMID: 14993393 PMCID: PMC2633129 DOI: 10.1124/mi.2.4.219] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Gender-based differences in the incidence of hypertensive and coronary artery disease, the development of atherosclerosis, and myocardial remodeling after infarction are attributable to the indirect effect of estrogen on risk factor profiles, such as cholesterol levels, glucose metabolism, and insulin levels. More recent evidence, however, suggests that activated estrogen receptor (ER) mediates signaling cascades that culminate in direct protective effects such as vasodilation, inhibition of response to vessel injury, limiting myocardial injury after infarction, and attenuating cardiac hypertrophy. Although the ER is usually thought of as a ligand-dependent transcription factor, it can also rapidly mobilize signals at the plasma membrane and in the cytoplasm. Thus, a greater understanding of ER function and regulation may lead to the development of highly specific therapeutics that mediate the prevention and treatment of cardiovascular diseases.
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Affiliation(s)
- Karen J Ho
- The Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Cambridge, MA 02139, USA
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Kawagoe J, Ohmichi M, Tsutsumi S, Ohta T, Takahashi K, Kurachi H. Mechanism of the divergent effects of estrogen on the cell proliferation of human umbilical endothelial versus aortic smooth muscle cells. Endocrinology 2007; 148:6092-9. [PMID: 17872375 DOI: 10.1210/en.2007-0188] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Diverse estrogen actions are controlled via estrogen receptors (ERs). Mechanisms of action of ERs are modulated by various factors such as ER subtypes, conformation of the ER-ligand complex, and recruitment of coregulator complexes to a target gene promoter. Estrogen exerts divergent actions on vascular cells; namely it increases endothelial cell and inhibits smooth muscle cell growth, resulting in a vasoprotective action. We particularly focused on these divergent effects and examined the mechanisms. The effects of raloxifene, which shows estrogen-like vasoprotective actions, were also examined. To examine the effects of 17beta-estradiol (E(2)) and raloxifene on human aortic smooth muscle cells (HASMCs) and human umbilical venous endothelial cells (HUVECs), we evaluated the effect of E(2) and raloxifene on transcriptional activity, recruitment of the coregulator complex to a target gene promoter, and acetylation of histone of both the IGF-I and COX-2 genes. Treatment with E(2) or raloxifene increased both IGF-I and cyclooxygenase (COX)-2 mRNA expression in HUVECs, whereas they attenuated the serum-induced increase of these genes in HASMCs. Treatment by E(2) and raloxifene induced recruitment of coactivator complex and histone acetylation at both the IGF-I and COX-2 gene promoter in HUVECs. In contrast, in HASMCs, E(2), and raloxifene attenuated the serum-induced recruitment of coactivator complexes and histone acetylation at both the IGF-I and COX-2 gene promoters. Estrogen and raloxifene exert divergent transcriptional regulation on both mRNA expression and the remodeling of IGF-I and COX-2 gene promoters in HUVECs vs. HASMCs.
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MESH Headings
- Acetylation/drug effects
- Aorta/cytology
- Blotting, Western
- Cell Proliferation/drug effects
- Cells, Cultured
- Cyclooxygenase 2/genetics
- Endothelial Cells/cytology
- Endothelial Cells/drug effects
- Endothelial Cells/metabolism
- Estradiol/pharmacology
- Estrogens/pharmacology
- Histone Acetyltransferases/genetics
- Histones/metabolism
- Humans
- Insulin-Like Growth Factor I/genetics
- Myocytes, Smooth Muscle/cytology
- Myocytes, Smooth Muscle/drug effects
- Myocytes, Smooth Muscle/metabolism
- Nuclear Receptor Coactivator 3
- Promoter Regions, Genetic/genetics
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- RNA, Small Interfering/genetics
- Raloxifene Hydrochloride/pharmacology
- Reverse Transcriptase Polymerase Chain Reaction
- Trans-Activators/genetics
- Transcription, Genetic/drug effects
- Transfection
- Umbilical Cord/cytology
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Affiliation(s)
- Jun Kawagoe
- Department of Obstetrics and Gynecology, Yamagata University School of Medicine, 2-2-2 Iidanishi, Yamagata, Japan
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Diez-Perez A. Selective estrogen receptor modulators (SERMS). ACTA ACUST UNITED AC 2007; 50:720-34. [PMID: 17117297 DOI: 10.1590/s0004-27302006000400017] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2006] [Accepted: 06/10/2006] [Indexed: 11/22/2022]
Abstract
Hormone receptors and, specifically, estrogen receptors were described about four decades ago. For estrogens, there are two receptors, estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta). The two receptors are coded by different genes and their tissue expression varies across organs. ERalpha is predominantly expressed in reproductive tissues (uterus, breast, ovaries) liver and central nervous system, whereas ERbeta is expressed in other tissues such as bone, endothelium, lungs, urogenital tract, ovaries, central nervous system and prostate. More than seventy molecules that belong to the SERMS class have been described. There are 5 chemical groups: triphenylethylenes, benzotiophenes, tetrahydronaphtylenes, indoles and benzopyrans. All of these non-hormonal compounds are capable of activating the ER, reduce bone turnover rate and, as an antiresorptive, clearly improve bone density. Estrogens reduce bone turnover rate and, as an antiresorptive, clearly improve bone density. They are also beneficial for the relief of menopausal symptoms. An ongoing debate that extends over the decades, relates to to overall benefit/risk profile of estrogen or estrogen-progestin therapy since these therapies can increase the risk of serious health disorders, such as breast cancer. SERMs have increased our understanding of hormone-receptor regulatory mechanisms. Their development has permitted a targeted efficacy profile avoiding some of the side effects of the hormone therapy. Their clinical utility relies today mostly on the effects on breast cancer and bone.
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Affiliation(s)
- Adolfo Diez-Perez
- Department of Internal Medicine, Autonomous University of Barcelona, Hospital del Mar-URFOA-IMIM, Barcelona, Spain.
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Leung FP, Tsang SY, Wong CM, Yung LM, Chan YC, Leung HS, Yao X, Huang Y. Raloxifene, tamoxifen and vascular tone. Clin Exp Pharmacol Physiol 2007; 34:809-13. [PMID: 17600563 DOI: 10.1111/j.1440-1681.2007.04684.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
1. Oestrogen deficiency causes progressive reduction in endothelial function. Despite the benefits of hormone-replacement therapy (HRT) evident in earlier epidemiological studies, recent randomized trials of HRT for the prevention of heart disease found no overall benefit. Instead, HRT users had higher incidences of stroke and heart attack. Most women discontinue HRT because of its many side-effects and/or the increased risk of breast and uterine cancer. This has contributed to the development of selective oestrogen receptor modulators (SERMs), such as tamoxifen and raloxifene, as alternative oestrogenic agents. 2. A SERM is a molecule that binds with high affinity to oestrogen receptors but has tissue-specific effects distinct from oestrogen, acting as an oestrogen agonist in some tissues and as an antagonist in others. Clinical and animal studies suggest multiple cardiovascular effects of SERMs. For example, raloxifene lowers serum levels of cholesterol and homocysteine, attenuates oxidation of low-density lipoprotein, inhibits endothelial-leucocyte interaction, improves endothelial function and reduces vascular smooth muscle tone. 3. Available evidence suggests that raloxifene and tamoxifen are capable of acting directly on both endothelial cells and the underlying vascular smooth muscle cells and cause a multitude of favourable modifications of the vascular wall, which jointly contribute to improved local blood flow. The outcome of the Raloxifene Use for the Heart (RUTH) trial will determine whether raloxifene, currently approved for the treatment of post-menopausal osteoporosis, could substitute for HRT in alleviating cardiovascular symptoms in post-menopausal women.
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Affiliation(s)
- Fung Ping Leung
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
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Leung FP, Yung LM, Leung HS, Au CL, Yao X, Vanhoutte PM, Laher I, Huang Y. Therapeutic concentrations of raloxifene augment nitric oxide-dependent coronary artery dilatation in vitro. Br J Pharmacol 2007; 152:223-9. [PMID: 17618301 PMCID: PMC1978259 DOI: 10.1038/sj.bjp.0707387] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND AND PURPOSE Raloxifene improves cardiovascular function. This study examines the hypothesis that therapeutic concentrations of raloxifene augment endothelium-dependent relaxation via up-regulation of eNOS expression and activity in porcine coronary arteries. EXPERIMENTAL APPROACH Isometric tension was measured in rings from isolated arteries. Intracellular Ca(2+) concentrations ([Ca(2+)](i)) in arterial endothelial cells were detected by Ca(2+) fluorescence imaging. Phosphorylation of eNOS at Ser-1177 was assayed by Western blot analysis. KEY RESULTS In arterial rings pre-contracted with 9,11-dideoxy-11alpha,9alpha-epoxy-methano-prostaglandin F(2alpha) (U46619), treatment with raloxifene (1-3 nM) augmented bradykinin- or substance P-induced relaxation and this effect was antagonized by ICI 182,780, an estrogen receptor antagonist. The enhanced relaxation was abolished in rings treated with inhibitors of nitric oxide/cyclic GMP-dependent dilation, N(G)-nitro-L-arginine methyl ester (L-NAME) plus 1H-[1,2,4]oxadizolo[4,3-a]quinoxalin-1-one (ODQ). In contrast, effects of raloxifene were unaffected after inhibition of endothelium-derived hyperpolarizing factors by charybdotoxin plus apamin. Raloxifene (3 nM) did not influence endothelium-independent relaxation to sodium nitroprusside. 17beta-Estradiol (3-10 nM) also enhanced bradykinin-induced relaxation, which was inhibited by ICI 182,780. Treatment with raloxifene (3 nM) did not affect bradykinin-stimulated rise in endothelial cell [Ca(2+)](i). Raloxifene, 17beta-estradiol, and bradykinin increased eNOS phosphorylation at Ser-1177 and ICI 182,780 prevented effects of raloxifene or 17beta-estradiol but not that of bradykinin. Raloxifene had neither additive nor antagonistic effects on 17beta-estradiol-induced eNOS phosphorylation. CONCLUSIONS AND IMPLICATIONS Raloxifene in therapeutically relevant concentrations augmented endothelial function in porcine coronary arteries in vitro through ICI 182,780-sensitive mechanisms that were associated with increased phosphorylation of eNOS but independent of changes in endothelial cell [Ca(2+)](i).
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Affiliation(s)
- F P Leung
- Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong Hong Kong SAR, China
- Department of Physiology, Chinese University of Hong Kong Hong Kong SAR, China
| | - L M Yung
- Department of Physiology, Chinese University of Hong Kong Hong Kong SAR, China
| | - H S Leung
- Department of Physiology, Chinese University of Hong Kong Hong Kong SAR, China
| | - C L Au
- Department of Physiology, Chinese University of Hong Kong Hong Kong SAR, China
| | - X Yao
- Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong Hong Kong SAR, China
- Department of Physiology, Chinese University of Hong Kong Hong Kong SAR, China
- Institute of Vascular Medicine, Chinese University of Hong Kong Hong Kong SAR, China
| | - P M Vanhoutte
- Department of Pharmacology, University of Hong Kong Hong Kong, China
| | - I Laher
- Department of Pharmacology and Therapeutics, University of British Columbia Vancouver, Canada
| | - Y Huang
- Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong Hong Kong SAR, China
- Department of Physiology, Chinese University of Hong Kong Hong Kong SAR, China
- Institute of Vascular Medicine, Chinese University of Hong Kong Hong Kong SAR, China
- Author for correspondence:
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Masiá S, Alvarez S, de Lera AR, Barettino D. Rapid, nongenomic actions of retinoic acid on phosphatidylinositol-3-kinase signaling pathway mediated by the retinoic acid receptor. Mol Endocrinol 2007; 21:2391-402. [PMID: 17595318 DOI: 10.1210/me.2007-0062] [Citation(s) in RCA: 136] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Retinoic acid (RA) treatment of SH-SY5Y neuroblastoma cells results in activation of phosphatidylinositol-3-kinase (PI3K) signaling pathway, and this activation is required for RA-induced differentiation. Here we show that RA activates PI3K and ERK1/2 MAPK signaling pathways through a rapid, nongenomic mechanism that does not require new gene transcription or newly synthesized proteins. Activation of PI3K by RA appears to involve the classical nuclear receptor, retinoic acid receptor (RAR), on the basis of the pharmacological profile of the activation, loss, and gain of function experiments with mouse embryo fibroblast-RAR(alpha beta gamma)(L-/L-) null cells, and the physical association between liganded RAR and PI3K activity. The association of RAR with the two subunits of PI3K was differentially regulated by the ligand. Immunoprecipitation experiments performed in SH-SY5Y cells showed stable association between RARalpha and p85, the regulatory subunit of PI3K, independently of the presence of RA. In contrast, ligand administration increased the association of p110, the catalytic subunit of PI3K, to this complex. The intracellular localization of RAR proved to be relevant for PI3K activation. A chimerical RAR fusing c-Src myristylation domain to the N terminus of RARalpha (Myr-RARalpha) was targeted to plasma membrane. Transfection of Myr-RARalpha to mouse embryo fibroblast-RAR(alpha beta gamma)(L-/L-) null cells and COS-7 cells results in strong activation of the PI3K signaling pathway, although both in the absence as well in the presence of RA. Our results support a mechanism in which ligand binding to RAR would play a major role in the assembly and intracellular location of a signaling complex involving RAR and the subunits of PI3K.
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Affiliation(s)
- Susana Masiá
- Biology of Hormone Action Unit, Department of Molecular and Cellular Pathology and Therapy, Instituto de Biomedicina de Valencia [Consejo Superior de Investigaciones Cientificas], E-46010 Valencia, Spain
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Cano A, Hermenegildo C, Oviedo P, Tarín JJ. Selective estrogen receptor modulators and risk for coronary heart disease. Climacteric 2007; 10:97-111. [PMID: 17453858 DOI: 10.1080/13697130701258804] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Coronary heart disease (CHD) is the leading cause of death in women in most countries. Atherosclerosis is the main biological process determining CHD. Clinical data support the notion that CHD is sensitive to estrogens, but debate exists concerning the effects of the hormone on atherosclerosis and its complications. Selective estrogen receptor modulators (SERMs) are compounds capable of binding the estrogen receptor to induce a functional profile distinct from estrogens. The possibility that SERMs may shift the estrogenic balance on cardiovascular risk towards a more beneficial profile has generated interest in recent years. There is considerable information on the effects of SERMs on distinct areas that are crucial in atherogenesis. The complexity derived from the diversity of variables affecting their mechanism of action plus the differences between compounds make it difficult to delineate one uniform trend for SERMs. The present picture, nonetheless, is one where SERMs seem less powerful than estrogens in atherosclerosis protection, but more gentle with advanced forms of the disease. The recent publication of the Raloxifene Use for The Heart (RUTH) study has confirmed a neutral effect for raloxifene. Prothrombotic states may favor occlusive thrombi at sites occupied by atheromatous plaques. Platelet activation has received attention as an important determinant of arterial thrombogenesis. Although still sparse, available evidence globally suggests neutral or beneficial effects for SERMs.
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Affiliation(s)
- A Cano
- Department of Pediatrics, Obstetrics and Gynecology, University of Valencia, Valencia, Spain
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Satoh M, Matter CM, Ogita H, Takeshita K, Wang CY, Dorn GW, Liao JK. Inhibition of apoptosis-regulated signaling kinase-1 and prevention of congestive heart failure by estrogen. Circulation 2007; 115:3197-204. [PMID: 17562954 PMCID: PMC2701741 DOI: 10.1161/circulationaha.106.657981] [Citation(s) in RCA: 86] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Epidemiological studies have shown gender differences in the incidence of congestive heart failure (CHF); however, the role of estrogen in CHF is not known. We hypothesize that estrogen prevents cardiomyocyte apoptosis and the development of CHF. METHODS AND RESULTS 17Beta-estradiol (E2, 0.5 mg/60-day release) or placebo pellet was implanted subcutaneously into male G alpha q transgenic (Gq) mice. After 8 weeks, E2 treatment decreased the extent of cardiac hypertrophy and dilation and improved contractility in Gq mice. E2 treatment also attenuated nicotinamide adenine dinucleotide phosphate oxidase activity and superoxide anion production via downregulation of Rac1. This correlated with reduced apoptosis in cardiomyocytes of Gq mice. The antioxidative properties of E2 were also associated with increased expression of thioredoxin (Trx), Trx reductases, and Trx reductase activity in the hearts of Gq mice. Furthermore, the activation of apoptosis signal-regulating kinase 1 and its downstream effectors, c-Jun N-terminal kinase and p38 mitogen-activated protein kinase, in the hearts of Gq mice was reduced by long-term E2 treatment. Indeed, E2 (10 nmol/L)-treated cardiomyocytes were much more resistant to angiotensin II-induced apoptosis. These antiapoptotic and cardioprotective effects of E2 were blocked by an estrogen receptor antagonist (ICI 182,780) and by a Trx reductase inhibitor (azelaic acid). CONCLUSIONS These findings indicate that long-term E2 treatment improves CHF by antioxidative mechanisms that involve the upregulation of Trx and inhibition of Rac1-mediated attenuated nicotinamide adenine dinucleotide phosphate oxidase activity and apoptosis signal-regulating kinase 1 /c-Jun N-terminal kinase/p38 mitogen-activated protein kinase-mediated apoptosis. These results suggest that estrogen may be a useful adjunctive therapy for patients with CHF.
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Affiliation(s)
- Minoru Satoh
- Vascular Medicine Research Unit, Brigham and Women's Hospital and Harvard Medical School, Cambridge, MA 02139, USA
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