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Li X, Wang J, Chen Y, Li P, Wen H, Xu X, Wang J, Xu Y, Chen Y, Song J, Lu W, Zhu D, Fu X. Estrogen Oppositely Regulates Pulmonary Hypertension via METTL3/PFKFB3 under Normoxia and Hypoxia. Am J Respir Cell Mol Biol 2025; 72:258-271. [PMID: 39265182 DOI: 10.1165/rcmb.2024-0042oc] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 09/12/2024] [Indexed: 09/14/2024] Open
Abstract
Despite extensive investigation into estrogen's role in pulmonary hypertension (PH) development, its effects, whether beneficial or detrimental, remain contentious. This study aimed to elucidate estrogen's potential role in PH under normoxic and hypoxic conditions. Using norfenfluramine- and hypoxia-induced rat models of PH, the study evaluated the impact of 17β-estradiol (E2) on PH progression. E2 promoted PH development under normoxia while providing protection under hypoxia. Mechanistically, under normoxia, E2 upregulated METTL3 (methyltransferase-like 3) gene transcription and protein via an estrogen response element-dependent pathway, which in turn increased the N6-methyladenosine methylation and translational efficiency of PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3) mRNA, leading to increased PFKFB3 protein levels and enhanced proliferation and migration of pulmonary artery smooth muscle cells. Conversely, under hypoxia, E2 downregulated METTL3 transcription through a hypoxia response element-dependent mechanism driven by increased HIF-1α (hypoxia-inducible factor 1α) levels, resulting in reduced PFKFB3 protein expression and diminished pulmonary artery smooth muscle cell proliferation and migration. METTL3 and PFKFB3 proteins are upregulated in the pulmonary arteries of patients with pulmonary arterial hypertension. Collectively, these findings suggest that E2 exerts differential effects on PH progression via dual regulation of the METTL3/PFKFB3 protein under normoxic and hypoxic conditions, positioning the METTL3/PFKFB3 protein as a potential therapeutic target for PH treatment.
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Affiliation(s)
- Xiaosa Li
- Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jiale Wang
- Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yuqin Chen
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; and
| | - Ping Li
- Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Hao Wen
- Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xingyan Xu
- Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jian Wang
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; and
| | - Yiming Xu
- Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yingying Chen
- Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jiangping Song
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wenju Lu
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; and
| | - Dongxing Zhu
- Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xiaodong Fu
- Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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Bai H, Varsanik MA, Thaxton C, Ohashi Y, Gonzalez L, Zhang W, Aoyagi Y, Kano M, Yatsula B, Li Z, Pocivavsek L, Dardik A. Disturbed flow in the juxta-anastomotic area of an arteriovenous fistula correlates with endothelial loss, acute thrombus formation, and neointimal hyperplasia. Am J Physiol Heart Circ Physiol 2024; 326:H1446-H1461. [PMID: 38578237 PMCID: PMC11380968 DOI: 10.1152/ajpheart.00054.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 02/27/2024] [Accepted: 03/28/2024] [Indexed: 04/06/2024]
Abstract
Clinical failure of arteriovenous neointimal hyperplasia (NIH) fistulae (AVF) is frequently due to juxta-anastomotic NIH (JANIH). Although the mouse AVF model recapitulates human AVF maturation, previous studies focused on the outflow vein distal to the anastomosis. We hypothesized that the juxta-anastomotic area (JAA) has increased NIH compared with the outflow vein. AVF was created in C57BL/6 mice without or with chronic kidney disease (CKD). Temporal and spatial changes of the JAA were examined using histology and immunofluorescence. Computational techniques were used to model the AVF. RNA-seq and bioinformatic analyses were performed to compare the JAA with the outflow vein. The jugular vein to carotid artery AVF model was created in Wistar rats. The neointima in the JAA shows increased volume compared with the outflow vein. Computational modeling shows an increased volume of disturbed flow at the JAA compared with the outflow vein. Endothelial cells are immediately lost from the wall contralateral to the fistula exit, followed by thrombus formation and JANIH. Gene Ontology (GO) enrichment analysis of the 1,862 differentially expressed genes (DEG) between the JANIH and the outflow vein identified 525 overexpressed genes. The rat jugular vein to carotid artery AVF showed changes similar to the mouse AVF. Disturbed flow through the JAA correlates with rapid endothelial cell loss, thrombus formation, and JANIH; late endothelialization of the JAA channel correlates with late AVF patency. Early thrombus formation in the JAA may influence the later development of JANIH.NEW & NOTEWORTHY Disturbed flow and focal endothelial cell loss in the juxta-anastomotic area of the mouse AVF colocalizes with acute thrombus formation followed by late neointimal hyperplasia. Differential flow patterns between the juxta-anastomotic area and the outflow vein correlate with differential expression of genes regulating coagulation, proliferation, collagen metabolism, and the immune response. The rat jugular vein to carotid artery AVF model shows changes similar to the mouse AVF model.
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MESH Headings
- Animals
- Neointima
- Hyperplasia
- Arteriovenous Shunt, Surgical
- Thrombosis/physiopathology
- Thrombosis/pathology
- Thrombosis/genetics
- Thrombosis/etiology
- Thrombosis/metabolism
- Mice, Inbred C57BL
- Rats, Wistar
- Male
- Jugular Veins/metabolism
- Jugular Veins/pathology
- Jugular Veins/physiopathology
- Disease Models, Animal
- Carotid Arteries/pathology
- Carotid Arteries/physiopathology
- Carotid Arteries/metabolism
- Carotid Arteries/surgery
- Mice
- Rats
- Regional Blood Flow
- Endothelium, Vascular/metabolism
- Endothelium, Vascular/physiopathology
- Endothelium, Vascular/pathology
- Renal Insufficiency, Chronic/pathology
- Renal Insufficiency, Chronic/physiopathology
- Renal Insufficiency, Chronic/genetics
- Renal Insufficiency, Chronic/metabolism
- Endothelial Cells/metabolism
- Endothelial Cells/pathology
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Affiliation(s)
- Hualong Bai
- Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, Connecticut, United States
- Department of Surgery, Yale School of Medicine, New Haven, Connecticut, United States
| | - M Alyssa Varsanik
- Section of Vascular Surgery, Department of Surgery, University of Chicago Medicine, Chicago, Illinois, United States
| | - Carly Thaxton
- Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, Connecticut, United States
- Department of Surgery, Yale School of Medicine, New Haven, Connecticut, United States
| | - Yuichi Ohashi
- Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, Connecticut, United States
- Department of Surgery, Yale School of Medicine, New Haven, Connecticut, United States
| | - Luis Gonzalez
- Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, Connecticut, United States
- Department of Surgery, Yale School of Medicine, New Haven, Connecticut, United States
| | - Weichang Zhang
- Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, Connecticut, United States
- Department of Surgery, Yale School of Medicine, New Haven, Connecticut, United States
| | - Yukihiko Aoyagi
- Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, Connecticut, United States
- Department of Surgery, Yale School of Medicine, New Haven, Connecticut, United States
| | - Masaki Kano
- Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, Connecticut, United States
- Department of Surgery, Yale School of Medicine, New Haven, Connecticut, United States
| | - Bogdan Yatsula
- Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, Connecticut, United States
- Department of Surgery, Yale School of Medicine, New Haven, Connecticut, United States
| | - Zhuo Li
- Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, Connecticut, United States
- Department of Surgery, Yale School of Medicine, New Haven, Connecticut, United States
| | - Luka Pocivavsek
- Section of Vascular Surgery, Department of Surgery, University of Chicago Medicine, Chicago, Illinois, United States
| | - Alan Dardik
- Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, Connecticut, United States
- Department of Surgery, Yale School of Medicine, New Haven, Connecticut, United States
- Department of Cellular and Molecular Physiology, Yale University; New Haven, Connecticut, United States
- Department of Surgery, VA Connecticut Healthcare Systems, West Haven, Connecticut, United States
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3
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Querio G, Antoniotti S, Geddo F, Tullio F, Penna C, Pagliaro P, Gallo MP. Ischemic heart disease and cardioprotection: Focus on estrogenic hormonal setting and microvascular health. Vascul Pharmacol 2021; 141:106921. [PMID: 34592428 DOI: 10.1016/j.vph.2021.106921] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 09/14/2021] [Accepted: 09/23/2021] [Indexed: 12/12/2022]
Abstract
Ischemic Heart Disease (IHD) is a clinical condition characterized by insufficient blood flow to the cardiac tissue, and the consequent inappropriate oxygen and nutrients supply and metabolic waste removal in the heart. In the last decade a broad scientific literature has underlined the distinct mechanism of onset and the peculiar progress of IHD between female and male patients, highlighting the estrogenic hormonal setting as a key factor of these sex-dependent divergences. In particular, estrogen-activated cardioprotective pathways exert a pivotal role for the microvascular health, and their impairment, both physiologically and pathologically driven, predispose to vascular dysfunctions. Aim of this review is to summarize the current knowledge on the estrogen receptors localization and function in the cardiovascular system, particularly focusing on sex-dependent differences in microvascular vs macrovascular dysfunction and on the experimental models that allowed the researchers to reach the current findings and sketching the leading estrogen-mediated cardioprotective mechanisms.
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Affiliation(s)
- Giulia Querio
- Department of Life Sciences and Systems Biology, University of Torino, Torino, Italy
| | - Susanna Antoniotti
- Department of Life Sciences and Systems Biology, University of Torino, Torino, Italy
| | - Federica Geddo
- Department of Life Sciences and Systems Biology, University of Torino, Torino, Italy
| | - Francesca Tullio
- Department of Clinical and Biological Sciences, University of Torino, Torino, Italy
| | - Claudia Penna
- Department of Clinical and Biological Sciences, University of Torino, Torino, Italy
| | - Pasquale Pagliaro
- Department of Clinical and Biological Sciences, University of Torino, Torino, Italy.
| | - Maria Pia Gallo
- Department of Life Sciences and Systems Biology, University of Torino, Torino, Italy.
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Chen J, Zhang X, Wang Y, Ye Y, Huang Z. Differential ability of formononetin to stimulate proliferation of endothelial cells and breast cancer cells via a feedback loop involving MicroRNA-375, RASD1, and ERα. Mol Carcinog 2018; 57:817-830. [PMID: 29722068 DOI: 10.1002/mc.22531] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2016] [Accepted: 07/24/2016] [Indexed: 01/12/2023]
Abstract
For postmenopausal cardiovascular disease, long-term estrogen therapy may increase the risk of breast cancer. To reduce this risk, estrogen may be replaced with the phytoestrogen formononetin, but how formononetin acts on vascular endothelial cells (ECs) and breast cancer cells is unclear. Here, we show that low concentrations of formononetin induced proliferation and inhibited apoptosis more strongly in cultured human umbilical vein endothelial cells (HUVECs) than in breast cancer cells expressing estrogen receptor α (ERα) (MCF-7, BT474) or not (MDA-MB-231), and that this differential stimulation was associated with miR-375 up-regulation in HUVECs. For the first time, we demonstrate the presence of a feedback loop involving miR-375, ras dexamethasone-induced 1 (RASD1), and ERα in normal HUVECs, and we show that formononetin stimulated this feedback loop in HUVECs but not in MCF-7 or BT474 cells. In all three cell lines, formononetin increased Akt phosphorylation and Bcl-2 expression. Inhibiting miR-375 blocked these changes and increased proliferation in HUVECs, but not in MCF-7 or BT474 cells. In ovariectomized rats, formononetin increased uterine weight and caused similar changes in levels of miR-375, RASD1, ERα, and Bcl-2 in aortic ECs as in cultured HUVECs. In mice bearing MCF-7 xenografts, tumor growth was stimulated by 17β-estradiol but not by formononetin. These results suggest selective action of formononetin in ECs (proliferation stimulation and apoptosis inhibition) relative to breast cancer cells, possibly via a feedback loop involving miR-375, RASD1, and ERα. This differential effect may explain why formononetin may not increase the risk of postmenopausal breast cancer.
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Affiliation(s)
- Jian Chen
- School of Basic Medical Sciences, Guilin Medical University, Guilin, China
| | - Xing Zhang
- School of Basic Medical Sciences, Guilin Medical University, Guilin, China
| | - Yong Wang
- School of Basic Medical Sciences, Guilin Medical University, Guilin, China
| | - Yu Ye
- Department of Emergency, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Zhaoquan Huang
- Department of Pathology, Guilin Medical University, Guilin, China
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Zhang Y, Qian X, Sun X, Lin C, Jing Y, Yao Y, Ma Z, Kuai M, Lu Y, Kong X, Chen Q, Wu X, Zhao X, Li Y, Bian H. Liuwei Dihuang, a traditional Chinese medicinal formula, inhibits proliferation and migration of vascular smooth muscle cells via modulation of estrogen receptors. Int J Mol Med 2018; 42:31-40. [PMID: 29693116 PMCID: PMC5979928 DOI: 10.3892/ijmm.2018.3622] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Accepted: 11/10/2017] [Indexed: 01/27/2023] Open
Abstract
The phenotypic modulation of vascular smooth muscle cells (VSMCs) serves an important role in atherosclerosis-induced vascular alterations, including vascular remodeling. However, the precise mechanisms underlying VSMC phenotypic modulation remain to be elucidated. Our previous study demonstrated that Liuwei Dihuang formula (LWDHF) could improve menopausal atherosclerosis by upregulating the expression of estrogen receptors (ERs). The present study examined the role of ERs in the effects of LWDHF on VSMC phenotypic modulation. VSMC proliferation and cell cycle progression were examined by MTT assay and flow cytometry, respectively. The expression levels of α-smooth muscle actin, osteopontin and ERs were determined using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. Cell ultrastructure was observed under an electron microscope. F-actin polymerization was detected by fluorescein isothiocyanate-phalloidin staining using fluorescence microscopy. A modified Boyden chamber assay was employed to assess VSMCs migration. Small interfering (si)RNA technology was used to examine the role of ERα in the effects of LWDHF on phenotypic modulation. The results indicated that LWDHF (3-12 µg/ml) inhibited proliferation and induced a cell cycle arrest in VSMCs treated with angiotensin II (Ang II; 100 nM) in a concentration-dependent manner. In addition, Ang II-stimulated migration of VSMCs and reorganization of actin were markedly inhibited by treatment with 12 µg/ml LWDHF. Results of RT-qPCR and western blotting demonstrated that LWDHF markedly stimulated transcription and expression of ERα and ERβ, and inhibited VSMC synthetic phenotype. Furthermore, LWDHF-induced inhibition of phenotypic switching was partially suppressed by tamoxifen, and transfection with ERα siRNA markedly abolished the effects of LWDHF on VSMC phenotypic switching. In conclusion, these results revealed that ERα served an important role in LWDHF-induced regulation of the VSMC phenotype, including proliferation and migration.
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Affiliation(s)
- Yayun Zhang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Xing Qian
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Xin Sun
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Chao Lin
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Yi Jing
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Yuan Yao
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Zhi Ma
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Meiyu Kuai
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Ying Lu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Xueyun Kong
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Qi Chen
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Xiang Wu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Xuan Zhao
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Yu Li
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Huimin Bian
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
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Pérez-Cremades D, Mompeón A, Vidal-Gómez X, Hermenegildo C, Novella S. miRNA as a New Regulatory Mechanism of Estrogen Vascular Action. Int J Mol Sci 2018; 19:ijms19020473. [PMID: 29415433 PMCID: PMC5855695 DOI: 10.3390/ijms19020473] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 01/31/2018] [Accepted: 02/01/2018] [Indexed: 01/01/2023] Open
Abstract
The beneficial effects of estrogen on the cardiovascular system have been reported extensively. In fact, the incidence of cardiovascular diseases in women is lower than in age-matched men during their fertile stage of life, a benefit that disappears after menopause. These sex-related differences point to sexual hormones, mainly estrogen, as possible cardiovascular protective factors. The regulation of vascular function by estrogen is mainly related to the maintenance of normal endothelial function and is mediated by both direct and indirect gene transcription through the activity of specific estrogen receptors. Some of these mechanisms are known, but many remain to be elucidated. In recent years, microRNAs have been established as non-coding RNAs that regulate the expression of a high percentage of protein-coding genes in mammals and are related to the correct function of human physiology. Moreover, within the cardiovascular system, miRNAs have been related to physiological and pathological conditions. In this review, we address what is known about the role of estrogen-regulated miRNAs and their emerging involvement in vascular biology.
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Affiliation(s)
- Daniel Pérez-Cremades
- Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, 46010 Valencia, Spain.
- INCLIVA Biomedical Research Institute, 46010 Valencia, Spain.
| | - Ana Mompeón
- Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, 46010 Valencia, Spain.
- INCLIVA Biomedical Research Institute, 46010 Valencia, Spain.
| | - Xavier Vidal-Gómez
- Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, 46010 Valencia, Spain.
- INCLIVA Biomedical Research Institute, 46010 Valencia, Spain.
| | - Carlos Hermenegildo
- Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, 46010 Valencia, Spain.
- INCLIVA Biomedical Research Institute, 46010 Valencia, Spain.
| | - Susana Novella
- Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, 46010 Valencia, Spain.
- INCLIVA Biomedical Research Institute, 46010 Valencia, Spain.
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7
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Chang CC, Lee WS, Chuang CL, Hsin IF, Hsu SJ, Chang T, Huang HC, Lee FY, Lee SD. Effects of raloxifene on portal hypertension and hepatic encephalopathy in cirrhotic rats. Eur J Pharmacol 2017; 802:36-43. [PMID: 28238769 DOI: 10.1016/j.ejphar.2017.02.039] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Revised: 02/22/2017] [Accepted: 02/22/2017] [Indexed: 01/13/2023]
Abstract
Raloxifene, a selective estrogen receptor modulator, has been used extensively for osteoporosis. In addition to the effect of osteoporosis treatment, emerging evidences show that raloxifene affects the vascular function in different tissues. Cirrhosis is characterized with portal hypertension and complicated with hepatic encephalopathy. Portal hypertension affects portal-systemic shunt which leads to hepatic encephalopathy that the vascular modulation might influence severity of hepatic encephalopathy. Herein, we evaluated the impact of raloxifene on bile duct ligation (BDL)-induced cirrhotic rats. The female Sprague-Dawley rats received BDL plus ovariectomy or sham-operation. Four weeks later, rats were divided into 2 subgroups respectively to receive of raloxifene (10mg/kg/day) or saline (vehicle) for 14 days. On the 43th day, motor activities and hemodynamic parameters were measured. Hepatic and vascular mRNA and protein expressions were determined. The histopathological change of liver was examined. We found that the liver biochemistry, ammonia level and motor activity were similar between cirrhotic rats with or without raloxifene administration. The hemodynamic parameters were not significantly different except that raloxifene reduced portal venous inflow. Raloxifene exacerbated hepatic fibrosis and up-regulated hepatic endothelin-1 and cyclooxygenase 2 protein expressions. In addition, raloxifene modulated the mRNA expressions of endothelial nitric oxide synthase, cyclooxygenase and endothelin-1 in the superior mesenteric artery and collateral vessel. In conclusion, raloxifene aggravates hepatic fibrosis and decreases portal venous inflow in cirrhotic rats without adversely affecting portal hypertension and hepatic encephalopathy. The modulation of hepatic and vascular endothelin-1, endothelial nitric oxide synthase and cyclooxygenase expressions may play a role in the mechanism.
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Affiliation(s)
- Ching-Chih Chang
- Division of General Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Wen-Shin Lee
- Division of General Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Chiao-Lin Chuang
- Division of General Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - I-Fang Hsin
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Endoscopy Center for Diagnosis and Treatment, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Shao-Jung Hsu
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Ting Chang
- Division of General Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Hui-Chun Huang
- Division of General Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
| | - Fa-Yauh Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
| | - Shou-Dong Lee
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Cheng-Hsin General Hospital, Taipei, Taiwan
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8
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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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Del Turco S, Sartini S, Sentieri C, Saponaro C, Navarra T, Dario B, Da Settimo F, La Motta C, Basta G. A novel 2,3-diphenyl-4H-pyrido[1,2-a]pyrimidin-4-one derivative inhibits endothelial cell dysfunction and smooth muscle cell proliferation/activation. Eur J Med Chem 2013; 72:102-9. [PMID: 24361522 DOI: 10.1016/j.ejmech.2013.11.021] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2013] [Revised: 11/14/2013] [Accepted: 11/21/2013] [Indexed: 11/24/2022]
Abstract
Hyper-proliferation and migration of vascular smooth muscle cells and endothelial cell dysfunction are central events in the development of neo-intimal lesions. Pursuing our interest in the synthesis of bioisosters of flavonoids, we studied in depth a novel synthetic 2,3-diphenyl-4H-pyrido[1,2-a]pyrimidin-4-one derivative, examining its effects in vitro on induced-cell proliferation and activation in human aortic smooth muscle cells (HAoSMCs) and in human umbilical vein endothelial cells (HUVECs). Compared with two well known flavonoids, apigenin and quercetin, the novel compound, 2-(3,4-dimethoxyphenyl)-3-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one, 3, was not toxic for HUVECs, even at high concentrations and for long incubation times, while the two flavonoids were not tolerated, even at concentrations as low as 10 μmol/L. Compound 3 inhibited selectively, and in a concentration-dependent manner, the proliferation of HAoSMCs but not that of HUVECs. In HUVECs, it inhibited the cytokine-induced vascular cell adhesion molecule-1 expression, but not the cyclooxygenase-2 (COX-2) expression. Instead, in HAoSMC, it inhibited the induction of COX-2 expression and the relative release of prostaglandin E2. In addition, it inhibited the transcription of the matrix metalloproteinase-9 and its activity. Thanks to its multiple and tissue-specific function, 2-(3,4-dimethoxyphenyl)-3-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one might replace or assist the action of current drugs eluted by coronary stents, in order to promote a functional repair of damaged wall.
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Affiliation(s)
- Serena Del Turco
- CNR, Institute of Clinical Physiology, Via G. Moruzzi, 1, 56124 Pisa, Italy
| | - Stefania Sartini
- Department of Pharmacy, University of Pisa, Via Bonanno, 6, 56126 Pisa, Italy
| | - Cassandra Sentieri
- CNR, Institute of Clinical Physiology, Via G. Moruzzi, 1, 56124 Pisa, Italy
| | - Chiara Saponaro
- CNR, Institute of Clinical Physiology, Via G. Moruzzi, 1, 56124 Pisa, Italy
| | - Teresa Navarra
- CNR, Institute of Clinical Physiology, Via G. Moruzzi, 1, 56124 Pisa, Italy
| | - Bianca Dario
- Department of Pharmacy, University of Pisa, Via Bonanno, 6, 56126 Pisa, Italy
| | - Federico Da Settimo
- Department of Pharmacy, University of Pisa, Via Bonanno, 6, 56126 Pisa, Italy
| | - Concettina La Motta
- Department of Pharmacy, University of Pisa, Via Bonanno, 6, 56126 Pisa, Italy.
| | - Giuseppina Basta
- CNR, Institute of Clinical Physiology, Via G. Moruzzi, 1, 56124 Pisa, Italy.
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10
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Khalil RA. Estrogen, vascular estrogen receptor and hormone therapy in postmenopausal vascular disease. Biochem Pharmacol 2013; 86:1627-42. [PMID: 24099797 DOI: 10.1016/j.bcp.2013.09.024] [Citation(s) in RCA: 92] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2013] [Revised: 09/25/2013] [Accepted: 09/25/2013] [Indexed: 02/07/2023]
Abstract
Cardiovascular disease (CVD) is less common in premenopausal women than men of the same age or postmenopausal women, suggesting vascular benefits of estrogen. Estrogen activates estrogen receptors ERα, ERβ and GPR30 in endothelium and vascular smooth muscle (VSM), which trigger downstream signaling pathways and lead to genomic and non-genomic vascular effects such as vasodilation, decreased VSM contraction and growth and reduced vascular remodeling. However, randomized clinical trials (RCTs), such as the Women's Health Initiative (WHI) and Heart and Estrogen/progestin Replacement Study (HERS), have shown little vascular benefits and even adverse events with menopausal hormone therapy (MHT), likely due to factors related to the MHT used, ER profile, and RCT design. Some MHT forms, dose, combinations or route of administration may have inadequate vascular effects. Age-related changes in ER amount, distribution, integrity and post-ER signaling could alter the vascular response to MHT. The subject's age, preexisting CVD, and hormone environment could also reduce the effects of MHT. Further evaluation of natural and synthetic estrogens, phytoestrogens, and selective estrogen-receptor modulators (SERMs), and the design of appropriate MHT combinations, dose, route and 'timing' could improve the effectiveness of conventional MHT and provide alternative therapies in the peri-menopausal period. Targeting ER using specific ER agonists, localized MHT delivery, and activation of specific post-ER signaling pathways could counter age-related changes in ER. Examination of the hormone environment and conditions associated with hormone imbalance such as polycystic ovary syndrome may reveal the causes of abnormal hormone-receptor interactions. Consideration of these factors in new RCTs such as the Kronos Early Estrogen Prevention Study (KEEPS) could enhance the vascular benefits of estrogen in postmenopausal CVD.
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Affiliation(s)
- Raouf A Khalil
- Vascular Surgery Research Laboratory, Division of Vascular and Endovascular Surgery, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA.
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11
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Wen J, Zhao Y, Li J, Weng C, Cai J, Yang K, Yuan H, Imperato-McGinley J, Zhu YS. Suppression of DHT-induced paracrine stimulation of endothelial cell growth by estrogens via prostate cancer cells. Prostate 2013; 73:1069-81. [PMID: 23423946 PMCID: PMC3923318 DOI: 10.1002/pros.22654] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2012] [Accepted: 01/23/2013] [Indexed: 11/08/2022]
Abstract
BACKGROUND Androgen modulation of angiogenesis in prostate cancer may be not directly mediated by androgen receptor (AR) as AR is not detected in the prostatic endothelial cells. METHODS We examined the paracrine stimulation of cell proliferation by prostate tumor cells and its modulation by androgen and estrogens in a murine endothelial cell line (MEC) that does not express AR. RESULTS Tumor cell conditioned media (TCM) collected from LAPC-4 or LNCaP prostatic tumor cells produced a time- and concentration-dependent induction of cell growth in MECs, which was parallel to the VEGF concentration in the TCM. This TCM-induced cell growth in MECs was enhanced by the treatment of prostatic tumor cells with dihydrotestosterone (DHT). Both the TCM-stimulation and DHT-enhancement effects in MECs were completely blocked by SU5416, a specific VEGF receptor antagonist. Co-administration of 17α-estradiol or 17β-estradiol with DHT in prostatic tumor cells completely inhibited the DHT-enhancement effect while treatment with DHT, 17α-estradiol or 17β-estradiol did not produce any significant direct effect in MECs. Moreover, administration of 17α-estradiol or 17β-estradiol in xenograft animals with LAPC-4 or LNCaP prostate tumor significantly decreased the microvessel number in the tumor tissues. CONCLUSIONS Our study indicated that prostate tumor cells regulate endothelial cell growth through a paracrine mechanism, which is mainly mediated by VEGF; and DHT is able to modulate endothelial cell growth via tumor cells, which is inhibited by 17α-estradiol and 17β-estradiol. Thus, both17α-estradiol and 17β-estradiol are potential agents for anti-angiogenesis therapy in androgen-responsive prostate cancer.
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Affiliation(s)
- Juan Wen
- Department of Medicine/Endocrinology, Weill Cornell Medical
College, NewYork, NewYork
- The Center of Clinical Pharmacology, Central South
University, Changsha, China
| | - Yuan Zhao
- Department of Medicine/Endocrinology, Weill Cornell Medical
College, NewYork, NewYork
| | - Jinghe Li
- Department of Medicine/Endocrinology, Weill Cornell Medical
College, NewYork, NewYork
| | - Chunyan Weng
- Department of Medicine/Endocrinology, Weill Cornell Medical
College, NewYork, NewYork
- The Center of Clinical Pharmacology, Central South
University, Changsha, China
| | - Jingjing Cai
- Department of Medicine/Endocrinology, Weill Cornell Medical
College, NewYork, NewYork
- The Center of Clinical Pharmacology, Central South
University, Changsha, China
| | - Kan Yang
- Department of Cardiology of the Third Xiangya Hospital,
Central South University, Changsha, China
| | - Hong Yuan
- The Center of Clinical Pharmacology, Central South
University, Changsha, China
| | | | - Yuan-Shan Zhu
- Department of Medicine/Endocrinology, Weill Cornell Medical
College, NewYork, NewYork
- The Institute of Clinical Pharmacology, Central South
University, Changsha, China
- Correspondence to: Yuan-Shan Zhu, Department of Medicine, Weill
Cornell Medical College, 1300 York Avenue, Box 149, New York, NY 10065.
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12
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Activation of GPER Induces Differentiation and Inhibition of Coronary Artery Smooth Muscle Cell Proliferation. PLoS One 2013; 8:e64771. [PMID: 23840305 PMCID: PMC3686788 DOI: 10.1371/journal.pone.0064771] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2012] [Accepted: 04/18/2013] [Indexed: 12/29/2022] Open
Abstract
Background Vascular pathology and dysfunction are direct life-threatening outcomes resulting from atherosclerosis or vascular injury, which are primarily attributed to contractile smooth muscle cells (SMCs) dedifferentiation and proliferation by re-entering cell cycle. Increasing evidence suggests potent protective effects of G-protein coupled estrogen receptor 1 (GPER) activation against cardiovascular diseases. However, the mechanism underlying GPER function remains poorly understood, especially if it plays a potential role in modulating coronary artery smooth muscle cells (CASMCs). Methodology/Principal Findings The objective of our study was to understand the functional role of GPER in CASMC proliferation and differentiation in coronary arteries using from humans and swine models. We found that the GPER agonist, G-1, inhibited both human and porcine CASMC proliferation in a concentration- (10−8 to 10−5 M) and time-dependent manner. Flow cytometry revealed that treatment with G-1 significantly decreased the proportion of S-phase and G2/M cells in the growing cell population, suggesting that G-1 inhibits cell proliferation by slowing progression of the cell cycle. Further, G-1-induced cell cycle retardation was associated with decreased expression of cyclin B, up-regulation of cyclin D1, and concomitant induction of p21, and partially mediated by suppressed ERK1/2 and Akt pathways. In addition, G-1 induces SMC differentiation evidenced by increased α-smooth muscle actin (α-actin) and smooth muscle protein 22α (SM22α) protein expressions and inhibits CASMC migration induced by growth medium. Conclusion GPER activation inhibits CASMC proliferation by suppressing cell cycle progression via inhibition of ERK1/2 and Akt phosphorylation. GPER may constitute a novel mechanism to suppress intimal migration and/or synthetic phenotype of VSMC.
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Herceg Z, Lambert MP, van Veldhoven K, Demetriou C, Vineis P, Smith MT, Straif K, Wild CP. Towards incorporating epigenetic mechanisms into carcinogen identification and evaluation. Carcinogenesis 2013; 34:1955-67. [PMID: 23749751 DOI: 10.1093/carcin/bgt212] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Remarkable progress in the field of epigenetics has turned academic, medical and public attention to the potential applications of these new advances in medicine and various fields of biomedical research. The result is a broader appreciation of epigenetic phenomena in the a etiology of common human diseases, most notably cancer. These advances also represent an exciting opportunity to incorporate epigenetics and epigenomics into carcinogen identification and safety assessment. Current epigenetic studies, including major international sequencing projects, are expected to generate information for establishing the 'normal' epigenome of tissues and cell types as well as the physiological variability of the epigenome against which carcinogen exposure can be assessed. Recently, epigenetic events have emerged as key mechanisms in cancer development, and while our search of the Monograph Volume 100 revealed that epigenetics have played a modest role in evaluating human carcinogens by the International Agency for Research on Cancer (IARC) Monographs so far, epigenetic data might play a pivotal role in the future. Here, we review (i) the current status of incorporation of epigenetics in carcinogen evaluation in the IARC Monographs Programme, (ii) potential modes of action for epigenetic carcinogens, (iii) current in vivo and in vitro technologies to detect epigenetic carcinogens, (iv) genomic regions and epigenetic modifications and their biological consequences and (v) critical technological and biological issues in assessment of epigenetic carcinogens. We also discuss the issues related to opportunities and challenges in the application of epigenetic testing in carcinogen identification and evaluation. Although the application of epigenetic assays in carcinogen evaluation is still in its infancy, important data are being generated and valuable scientific resources are being established that should catalyse future applications of epigenetic testing.
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Affiliation(s)
- Zdenko Herceg
- International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, F-69008 Lyon, France
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14
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Han G, Li F, Yu X, White RE. GPER: a novel target for non-genomic estrogen action in the cardiovascular system. Pharmacol Res 2013; 71:53-60. [PMID: 23466742 DOI: 10.1016/j.phrs.2013.02.008] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2012] [Revised: 02/19/2013] [Accepted: 02/20/2013] [Indexed: 12/17/2022]
Abstract
A key to harnessing the enormous therapeutic potential of estrogens is understanding the diversity of estrogen receptors and their signaling mechanisms. In addition to the classic nuclear estrogen receptors (i.e., ERα and ERβ), over the past decade a novel G-protein-coupled estrogen receptor (GPER) has been discovered in cancer and other cell types. More recently, this non-genomic signaling mechanism has been found in blood vessels, and mediates vasodilatory responses to estrogen and estrogen-like agents; however, downstream signaling events involved acute estrogen action remain unclear. The purpose of this review is to discuss the latest knowledge concerning GPER modulation of cardiovascular function, with a particular emphasis upon how activation of this receptor could mediate acute estrogen effects in the heart and blood vessels (i.e., vascular tone, cell growth and differentiation, apoptosis, endothelial function, myocardial protection). Understanding the role of GPER in estrogen signaling may help resolve some of the controversies associated with estrogen and cardiovascular function. Moreover, a more thorough understanding of GPER function could also open significant opportunities for the development of new pharmacological strategies that would provide the cardiovascular benefits of estrogen while limiting the potentially dangerous side effects.
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Affiliation(s)
- Guichun Han
- Women's Health Division, Michael E. DeBakey Institute, College Station, TX 77843, USA.
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15
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Reslan OM, Khalil RA. Vascular effects of estrogenic menopausal hormone therapy. Rev Recent Clin Trials 2012; 7:47-70. [PMID: 21864249 DOI: 10.2174/157488712799363253] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2011] [Revised: 07/22/2011] [Accepted: 07/29/2011] [Indexed: 12/21/2022]
Abstract
Cardiovascular disease (CVD) is more common in men and postmenopausal women (Post-MW) than premenopausal women (Pre-MW). Despite recent advances in preventive measures, the incidence of CVD in women has shown a rise that matched the increase in the Post-MW population. The increased incidence of CVD in Post-MW has been related to the decline in estrogen levels, and hence suggested vascular benefits of endogenous estrogen. Experimental studies have identified estrogen receptor ERα, ERβ and a novel estrogen binding membrane protein GPR30 (GPER) in blood vessels of humans and experimental animals. The interaction of estrogen with vascular ERs mediates both genomic and non-genomic effects. Estrogen promotes endothelium-dependent relaxation by increasing nitric oxide, prostacyclin, and hyperpolarizing factor. Estrogen also inhibits the mechanisms of vascular smooth muscle (VSM) contraction including [Ca2+]i, protein kinase C and Rho-kinase. Additional effects of estrogen on the vascular cytoskeleton, extracellular matrix, lipid profile and the vascular inflammatory response have been reported. In addition to the experimental evidence in animal models and vascular cells, initial observational studies in women using menopausal hormonal therapy (MHT) have suggested that estrogen may protect against CVD. However, randomized clinical trials (RCTs) such as the Heart and Estrogen/ progestin Replacement Study (HERS) and the Women's Health Initiative (WHI), which examined the effects of conjugated equine estrogens (CEE) in older women with established CVD (HERS) or without overt CVD (WHI), failed to demonstrate protective vascular effects of estrogen treatment. Despite the initial set-back from the results of MHT RCTs, growing evidence now supports the 'timing hypothesis', which suggests that MHT could increase the risk of CVD if started late after menopause, but may produce beneficial cardiovascular effects in younger women during the perimenopausal period. The choice of an appropriate MHT dose, route of administration, and estrogen/progestin combination could maximize the vascular benefits of MHT and minimize other adverse effects, especially if given within a reasonably short time after menopause to women that seek MHT for the relief of menopausal symptoms.
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Affiliation(s)
- Ossama M Reslan
- Vascular Surgery Research Laboratory, Division of Vascular and Endovascular Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA
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16
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Vassalle C, Simoncini T, Chedraui P, Pérez-López FR. Why sex matters: the biological mechanisms of cardiovascular disease. Gynecol Endocrinol 2012; 28:746-51. [PMID: 22329808 DOI: 10.3109/09513590.2011.652720] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Cardiovascular disease (CVD) is the leading determinant of mortality and morbidity in women. However, a full understanding of the basic and clinical aspects of CVD in women is far from being accomplished. Sexual dimorphism in CVD has been reported both in humans and experimental animals. Menopause is a risk factor for CVD due to the reduction of endogenous estrogen, although the mechanisms underlying are poorly understood. Estrogens act through binding to vascular estrogen receptors and by non-genomic mechanisms. Advances in this field are essential to improve CVD diagnostic and clinical strategies in women, and to develop sex-specific prevention plans as much as female-oriented treatment algorithms. This paper reviews pathophysiology of CVD in women and its potential clinical implications. Particular emphasis is given to biochemical markers and to indicators of cardiovascular dysfunction and damage. Estimation of these parameters, central to cardiovascular pathophysiology, could represent a particularly relevant tool in female patients. More research is needed to identify women who will profit most of early intervention.
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Affiliation(s)
- Cristina Vassalle
- G. Monasterio Foundation of the Toscana Region and Institute of Clinical Physiology-CNR, Pisa, Italy
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Abstract
Estrogens not only play a pivotal role in sexual development but are also involved in several physiological processes in various tissues including vasculature. While several epidemiological studies documented an inverse relationship between plasma estrogen levels and the incidence of cardiovascular disease and related it to the inhibition of atherosclerosis, an interventional trial showed an increase in cardiovascular events among postmenopausal women on estrogen treatment. The development of atherosclerotic lesions involves complex interplay between various pro- or anti-atherogenic processes that can be effectively studied only in vivo in appropriate animal models. With the advent of genetic engineering, transgenic mouse models of atherosclerosis have supplemented classical dietary cholesterol-induced disease models such as the cholesterol-fed rabbit. In the last two decades, these models were widely applied along with in vitro cell systems to specifically investigate the influence of estrogens on the development of early and advanced atherosclerotic lesions. The present review summarizes the results of these studies and assesses their contribution toward better understanding of molecular mechanisms underlying anti- and/or pro-atherogenic effects of estrogens in humans.
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Affiliation(s)
- Jerzy-Roch Nofer
- Center for Laboratory Medicine, University Hospital Münster, Albert Schweizer Campus 1, Gebäude A1, 48129 Münster, Germany.
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Pascua P, Camello-Almaraz C, Pozo MJ, Martin-Cano FE, Vara E, Fernández-Tresguerres JA, Camello PJ. Aging-induced alterations in female rat colon smooth muscle: the protective effects of hormonal therapy. J Physiol Biochem 2011; 68:255-62. [DOI: 10.1007/s13105-011-0138-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2011] [Accepted: 12/03/2011] [Indexed: 10/14/2022]
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Abstract
CVD (cardiovascular disease) is the leading cause of death for women. Considerable progress has been made in both our understanding of the complexities governing menopausal hormone therapy and our understanding of the cellular and molecular mechanisms underlying hormone and hormone receptor function. Understanding the interplay of atherosclerosis and sex steroid hormones and their cognate receptors at the level of the vessel wall has important ramifications for clinical practice. In the present review, we discuss the epidemiology of CVD in men and women, the clinical impact of sex hormones on CVD, and summarize our current understanding of the pathogenesis of atherosclerosis with a focus on gender differences in CVD, its clinical presentation and course, and pathobiology. The critical animal and human data that pertain to the role of oestrogens, androgens and progestins on the vessel wall is also reviewed, with particular attention to the actions of sex hormones on each of the three key cell types involved in atherogenesis: the endothelium, smooth muscle cells and macrophages. Where relevant, the systemic (metabolic) effects of sex hormones that influence atherogenesis, such as those involving vascular reactivity, inflammation and lipoprotein metabolism, are discussed. In addition, four key current concepts in the field are explored: (i) total hormone exposure time and coronary heart disease risk; (ii) the importance of tissue specificity of sex steroid hormones, critical timing and the stage of atherosclerosis in hormone action; (iii) biomarkers for atherosclerosis with regard to hormone therapy; and (iv) the complex role of sex steroids in inflammation. Future studies in this field will contribute to guiding clinical treatment recommendations for women and help define research priorities.
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Ai N, Krasowski MD, Welsh WJ, Ekins S. Understanding nuclear receptors using computational methods. Drug Discov Today 2009; 14:486-94. [PMID: 19429508 DOI: 10.1016/j.drudis.2009.03.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2008] [Revised: 03/03/2009] [Accepted: 03/04/2009] [Indexed: 02/06/2023]
Abstract
Nuclear receptors (NRs) are important targets for therapeutic drugs. NRs regulate transcriptional activities through binding to ligands and interacting with several regulating proteins. Computational methods can provide insights into essential ligand-receptor and protein-protein interactions. These in turn have facilitated the discovery of novel agonists and antagonists with high affinity and specificity as well as have aided in the prediction of toxic side effects of drugs by identifying possible off-target interactions. Here, we review the application of computational methods toward several clinically important NRs (with special emphasis on PXR) and discuss their use for screening and predicting the toxic side effects of xenobiotics.
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Affiliation(s)
- Ni Ai
- Department of Pharmacology, Robert Wood Johnson Medical School, University of Medicine & Dentistry of New Jersey, Piscataway, NJ 08854, USA
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