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Cignarella A, Bolego C, Barton M. Sex and sex steroids as determinants of cardiovascular risk. Steroids 2024; 206:109423. [PMID: 38631602 DOI: 10.1016/j.steroids.2024.109423] [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: 12/21/2023] [Revised: 04/08/2024] [Accepted: 04/14/2024] [Indexed: 04/19/2024]
Abstract
There are considerable sex differences regarding the risk of cardiovascular disease (CVD), including arterial hypertension, coronary artery disease (CAD) and stroke, as well as chronic renal disease. Women are largely protected from these conditions prior to menopause, and the risk increases following cessation of endogenous estrogen production or after surgical menopause. Cardiovascular diseases in women generally begin to occur at a later age than in men (on average with a delay of 10 years). Cessation of estrogen production also impacts metabolism, increasing the risk of developing obesity and diabetes. In middle-aged individuals, hypertension develops earlier and faster in women than in men, and smoking increases cardiovascular risk to a greater degree in women than it does in men. It is not only estrogen that affects female cardiovascular health and plays a protective role until menopause: other sex hormones such as progesterone and androgen hormones generate a complex balance that differentiates heart and blood vessel function in women compared to men. Estrogens improve vasodilation of epicardial coronary arteries and the coronary microvasculature by augmenting the release of vasodilating factors such as nitric oxide and prostacyclin, which are mechanisms of coronary vasodilatation that are more pronounced in women compared to men. Estrogens are also powerful inhibitors of inflammation, which in part explains their protective effects on CVD and chronic renal disease. Emerging evidence suggests that sex chromosomes also play a significant role in shaping cardiovascular risk. The cardiovascular protection conferred by endogenous estrogens may be extended by hormone therapy, especially using bioidentical hormones and starting treatment early after menopause.
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Affiliation(s)
| | - Chiara Bolego
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
| | - Matthias Barton
- Molecular Internal Medicine, University of Zürich, Zürich, Switzerland; Andreas Grüntzig Foundation, Zürich, Switzerland.
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Enright S, Werstuck GH. Investigating the Effects of Sex Hormones on Macrophage Polarization. Int J Mol Sci 2024; 25:951. [PMID: 38256027 PMCID: PMC10816176 DOI: 10.3390/ijms25020951] [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: 12/14/2023] [Revised: 12/29/2023] [Accepted: 01/08/2024] [Indexed: 01/24/2024] Open
Abstract
Sex differences in the development and progression of cardiovascular disease are well established, but the effects of sex hormones on macrophage polarization and pro-atherogenic functions are not well described. We hypothesize that sex hormones directly modulate macrophage polarization, and thereby regulate the progression of atherosclerosis. Bone marrow-derived monocytes from adult male and female C57BL/6 mice were differentiated into macrophages using macrophage colony-stimulating factor (20 ng/mL) and pre-treated with either 17β-estradiol (100 nM), testosterone (100 nM), or a vehicle control for 24 h. Macrophages were polarized into pro- or anti-inflammatory phenotypes and the effects of sex hormone supplementation on the gene expression of macrophage phenotypic markers were assessed using RT-qPCR. Inflammatory markers, including IL-1β, were quantified using an addressable laser bead immunoassay. A transwell migration assay was used to determine changes in macrophage migration. Sex differences were observed in macrophage polarization, inflammatory responses, and migration. Pre-treatment with 17β-estradiol significantly impaired the gene expression of inflammatory markers and the production of IL-1β in inflammatory macrophages. In anti-inflammatory macrophages, 17β-estradiol significantly upregulated the expression of anti-inflammatory markers and enhanced migration. Pre-treatment with testosterone enhanced anti-inflammatory mRNA expression and impaired the production of IL-1β. Our observations suggest a protective role of 17β-estradiol in atherogenesis that may contribute to the sexual dimorphisms in cardiovascular disease observed in human patients.
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Affiliation(s)
- Sophie Enright
- Thrombosis and Atherosclerosis Research Institute, 237 Barton Street E, Hamilton, ON L8L 2X2, Canada;
| | - Geoff H. Werstuck
- Thrombosis and Atherosclerosis Research Institute, 237 Barton Street E, Hamilton, ON L8L 2X2, Canada;
- Department of Medicine, McMaster University, 1280 Main St. W, Hamilton, ON L8S 4L8, Canada
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Hao H, Li Z, Qiao SY, Qi Y, Xu XY, Si JY, Liu YH, Chang L, Shi YF, Xu B, Wei ZH, Kang LN. Empagliflozin ameliorates atherosclerosis via regulating the intestinal flora. Atherosclerosis 2023; 371:32-40. [PMID: 36990029 DOI: 10.1016/j.atherosclerosis.2023.03.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 03/07/2023] [Accepted: 03/14/2023] [Indexed: 03/31/2023]
Abstract
BACKGROUND AND AIMS Sodium-glucose cotransporter 2 inhibitor (SGLT2i) has been reported to attenuate atherosclerosis. Further, it has been suggested that intestinal flora influences atherosclerosis progression. Herein we aimed to investigate whether SGLT2i can alleviate atherosclerosis through intestinal flora. METHODS Six-week-old male ApoE-/- mice fed a high-fat diet were gavaged either empagliflozin (SGLT2i group, n = 9) or saline (Ctrl group, n = 6) for 12 weeks. Feces were collected from both groups at the end of the experiment for fecal microbiota transplantation (FMT). Another 12 six-week-old male ApoE-/- mice were fed a high-fat diet and received FMT with feces either from SGLT2i (FMT-SGLT2i group, n = 6) or from Ctrl (FMT-Ctrl group, n = 6) groups. Blood, tissue, and fecal samples were collected for subsequent analyses. RESULTS In comparison with Ctrl group, atherosclerosis was less severe in the SGLT2i group (p < 0.0001), and the richness of probiotic, such as f_Coriobacteriaceae, f_S24-7, f_Lachnospiraceae, and f_Adlercreutzia, was higher in feces. Besides, empagliflozin resulted in a significant reduction in the inflammatory response and altered intestinal flora metabolism. Interestingly, compared with FMT-Ctrl, FMT-SGLT2i also showed a reduction in atherosclerosis and systemic inflammatory response, as well as changes in the component of intestinal flora and pertinent metabolites similar to SGLT2i group. CONCLUSIONS Empagliflozin seems to mitigate atherosclerosis partly by regulating intestinal microbiota, and this anti-atherosclerotic effect can be transferred through intestinal flora transplantation.
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Affiliation(s)
- Han Hao
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Cardiology, Affiliated Drum Tower Hospital, Medical School, Nanjing University, No.321, Zhongshan Road, Nanjing, 210008, China
| | - Zhu Li
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Cardiology, Affiliated Drum Tower Hospital, Medical School, Nanjing University, No.321, Zhongshan Road, Nanjing, 210008, China
| | - Shi-Yang Qiao
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Cardiology, Affiliated Drum Tower Hospital, Medical School, Nanjing University, No.321, Zhongshan Road, Nanjing, 210008, China
| | - Yu Qi
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Cardiology, Affiliated Drum Tower Hospital, Medical School, Nanjing University, No.321, Zhongshan Road, Nanjing, 210008, China
| | - Xiao-Ying Xu
- Department of Cardiology, Nanjing Drum Hospital, Nanjing University of Chinese Medicine, No.138, Xian-Lin Avenue, Nanjing, 210008, China
| | - Jia-Yi Si
- Department of Cardiology, Nanjing Drum Hospital, Nanjing University of Chinese Medicine, No.138, Xian-Lin Avenue, Nanjing, 210008, China
| | - Yi-Hai Liu
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Cardiology, Affiliated Drum Tower Hospital, Medical School, Nanjing University, No.321, Zhongshan Road, Nanjing, 210008, China
| | - Lei Chang
- Department of Cardiology, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, 210008, Jiangsu, China
| | - Yi-Fan Shi
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Cardiology, Affiliated Drum Tower Hospital, Medical School, Nanjing University, No.321, Zhongshan Road, Nanjing, 210008, China
| | - Biao Xu
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Cardiology, Affiliated Drum Tower Hospital, Medical School, Nanjing University, No.321, Zhongshan Road, Nanjing, 210008, China.
| | - Zhong-Hai Wei
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Cardiology, Affiliated Drum Tower Hospital, Medical School, Nanjing University, No.321, Zhongshan Road, Nanjing, 210008, China.
| | - Li-Na Kang
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Cardiology, Affiliated Drum Tower Hospital, Medical School, Nanjing University, No.321, Zhongshan Road, Nanjing, 210008, China.
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Arabacı Tamer S, Altınoluk T, Emran M, Korkmaz S, Yüksel RG, Baykal Z, Dur ZS, Levent HN, Ural MA, Yüksel M, Çevik Ö, Ercan F, Yıldırım A, Yeğen BÇ. Melatonin Alleviates Ovariectomy-Induced Cardiovascular Inflammation in Sedentary or Exercised Rats by Upregulating SIRT1. Inflammation 2022; 45:2202-2222. [PMID: 35665875 DOI: 10.1007/s10753-022-01685-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 04/25/2022] [Accepted: 05/16/2022] [Indexed: 11/28/2022]
Abstract
We aimed to evaluate the impact of hormone replacement, melatonin, or exercise alone or their combination on oxidative damage and functional status of heart, brain, and aorta of ovariectomized (OVX) rats and to determine whether the signaling pathway is dependent on sirtuin-1 (SIRT1). Ovariectomized Sprague Dawley rats were orally given either a hormone replacement therapy (1 mg/kg/day,17β estradiol; HRT) or melatonin (4 mg/kg/day) or HRT + melatonin treatments or tap water, while each group was further divided into sedentary and exercise (30 min/5 days/week) groups. After the heart rate measurements and memory tests were performed, trunk blood was collected at the end of the 10th week to determine metabolic parameters in serum samples. Tissue samples of abdominal aorta, heart, and brain were taken for biochemical measurements and histopathological evaluation. Heart rates and memory performances of the OVX rats were not changed significantly by none of the applications. Melatonin treatment or its co-administration with HRT upregulated the expressions of IL-10 and SIRT1, reduced the expressions of IL-6 and TNF-α, and reduced DNA damage in the hearts and thoracic aortae of non-exercised rats. Co-administration of melatonin and HRT to exercised OVX rats reduced inflammatory response and upregulated SIRT1 expression in the aortic and cardiac tissues. The present study suggests that melatonin treatment, either alone or in combination with exercise and/or HRT, upregulates SIRT1 expression and alleviates oxidative injury and inflammation in the hearts and aortas of OVX rats. Melatonin should be considered in alleviating cardiovascular disease risk in postmenopausal women.
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Affiliation(s)
- Sevil Arabacı Tamer
- Department of Physiology, Marmara University School of Medicine, Basibüyük Mah. Maltepe Basibüyük Yolu No. 9/1, 34854, Maltepe, Istanbul, Turkey.,Department of Physiology, Sakarya University School of Medicine, Sakarya, Turkey.,Department of Physiology, Marmara University Institute of Health Sciences, Istanbul, Turkey
| | - Tülin Altınoluk
- Department of Physiology, Marmara University School of Medicine, Basibüyük Mah. Maltepe Basibüyük Yolu No. 9/1, 34854, Maltepe, Istanbul, Turkey.,Department of Physiology, Marmara University Institute of Health Sciences, Istanbul, Turkey
| | - Miray Emran
- Marmara University School of Medicine, Istanbul, Turkey
| | - Seda Korkmaz
- Marmara University School of Medicine, Istanbul, Turkey
| | | | - Zeynep Baykal
- Marmara University School of Medicine, Istanbul, Turkey
| | | | - Hilal Nişva Levent
- Department of Histology & Embryology, Marmara University School of Medicine, Istanbul, Turkey
| | - Mürüvvet Abbak Ural
- Department of Biochemistry, Faculty of Medicine, Aydın Adnan Menderes University, Aydın, Turkey
| | - Meral Yüksel
- Marmara University Vocational School of Health Sciences, Istanbul, Turkey
| | - Özge Çevik
- Department of Biochemistry, Faculty of Medicine, Aydın Adnan Menderes University, Aydın, Turkey
| | - Feriha Ercan
- Department of Histology & Embryology, Marmara University School of Medicine, Istanbul, Turkey
| | - Alper Yıldırım
- Department of Physiology, Marmara University School of Medicine, Basibüyük Mah. Maltepe Basibüyük Yolu No. 9/1, 34854, Maltepe, Istanbul, Turkey
| | - Berrak Ç Yeğen
- Department of Physiology, Marmara University School of Medicine, Basibüyük Mah. Maltepe Basibüyük Yolu No. 9/1, 34854, Maltepe, Istanbul, Turkey.
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All-trans-retinoic acid ameliorates atherosclerosis, promotes perivascular adipose tissue browning, and increases adiponectin production in Apo-E mice. Sci Rep 2021; 11:4451. [PMID: 33627760 PMCID: PMC7904836 DOI: 10.1038/s41598-021-83939-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 02/09/2021] [Indexed: 01/31/2023] Open
Abstract
All-trans-retinoic acid (atRA), an active metabolite of vitamin A, exerts a potential role in the prevention of cardiovascular diseases. It has been shown that atRA ameliorates atherosclerosis while the exact mechanism underlying this protection remains unknown. This study investigated the influence of atRA on insulin resistance (IR), atherosclerosis, and the process of perivascular adipose tissue (PVAT) browning. Moreover, syntheses of adiponectin, adipokine with anti-atherogenic effects, and tumor necrosis factor-alpha (TNF-α), a pro-inflammatory cytokine, were determined in PVAT. Apolipoprotein E-deficient mice (Apo-E) and control C57BL/6J wild-type mice were treated with atRA (5 mg/kg/day) or vehicle (corn oil) by plastic feeding tubes for 8 weeks. Long-term atRA treatment in Apo-E mice did not affect insulin resistance. AtRa administration ameliorated atherosclerosis, induced PVAT browning, and increased adiponectin production in PVAT in Apo-E mice. Furthermore, atRA increased nitric oxide (NO) level but did not affect adiponectin concentration in the aorta of Apo-E mice. These results indicate that atRA ameliorates atherosclerosis in Apo-E mice. We also observed the browning of PVAT. Besides, atRA increased the synthesis of adiponectin in PVAT and augmented NO level in the aorta in ApoE mice.
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Freiin von Hövel F, Kefalakes E, Grothe C. What Can We Learn from FGF-2 Isoform-Specific Mouse Mutants? Differential Insights into FGF-2 Physiology In Vivo. Int J Mol Sci 2020; 22:ijms22010390. [PMID: 33396566 PMCID: PMC7795026 DOI: 10.3390/ijms22010390] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 12/29/2020] [Accepted: 12/29/2020] [Indexed: 12/16/2022] Open
Abstract
Fibroblast growth factor 2 (FGF-2), ubiquitously expressed in humans and mice, is functionally involved in cell growth, migration and maturation in vitro and in vivo. Based on the same mRNA, an 18-kilo Dalton (kDa) FGF-2 isoform named FGF-2 low molecular weight (FGF-2LMW) isoform is translated in humans and rodents. Additionally, two larger isoforms weighing 21 and 22 kDa also exist, summarized as the FGF-2 high molecular weight (FGF-2HMW) isoform. Meanwhile, the human FGF-2HMW comprises a 22, 23, 24 and 34 kDa protein. Independent studies verified a specific intracellular localization, mode of action and tissue-specific spatiotemporal expression of the FGF-2 isoforms, increasing the complexity of their physiological and pathophysiological roles. In order to analyze their spectrum of effects, FGF-2LMW knock out (ko) and FGF-2HMWko mice have been generated, as well as mice specifically overexpressing either FGF-2LMW or FGF-2HMW. So far, the development and functionality of the cardiovascular system, bone formation and regeneration as well as their impact on the central nervous system including disease models of neurodegeneration, have been examined. This review provides a summary of the studies characterizing the in vivo effects modulated by the FGF-2 isoforms and, thus, offers a comprehensive overview of its actions in the aforementioned organ systems.
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Affiliation(s)
- Friederike Freiin von Hövel
- Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Carl-Neuberg-Straße 1, D-30625 Hannover, Germany;
- Center for Systems Neuroscience (ZSN), University of Veterinary Medicine, Bünteweg 2, D-30559 Hannover, Germany;
| | - Ekaterini Kefalakes
- Center for Systems Neuroscience (ZSN), University of Veterinary Medicine, Bünteweg 2, D-30559 Hannover, Germany;
| | - Claudia Grothe
- Center for Systems Neuroscience (ZSN), University of Veterinary Medicine, Bünteweg 2, D-30559 Hannover, Germany;
- Correspondence: ; Tel.: +49-511-532-2897; Fax: +49-511-532-2880
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Wang X, Zhang J, Chen W, Tang Y, Zhou Y, Chen Y, Huang Y, Liu D. Study on the Effects of Estradiol in Staphylococcus epidermidis Device-Related Capsule Formation. Aesthetic Plast Surg 2020; 44:558-569. [PMID: 31832737 DOI: 10.1007/s00266-019-01567-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 11/29/2019] [Indexed: 10/25/2022]
Abstract
BACKGROUND Capsular contracture, mainly caused by Staphylococcus epidermidis (S. epidermidis) biofilm formation, is a complex problem for breast cancer patients who undergo surgical prosthetic breast reconstruction. Estradiol has been reported to be involved in the formation of bacterial biofilms. Thus, the underlying mechanism of estradiol in capsular contracture needs to be investigated. METHODS Biofilm-related gene expressions were measured by qRT-PCR after sterilizing the silicone with bacterial suspension and E2 treatment in vitro. Rat models were established with bilateral ovariectomy operations and estradiol subcutaneous injections. The effects of estradiol on capsular contracture were detected by monitoring serum estradiol levels, bacterial infection rate in organs, biofilm formation and capsular contracture in vivo; inflammatory factors in vivo were examined as well. Biofilm on the silicone implants was observed under a scanning electron microscope. RESULTS Both positive regulatory genes and negative regulatory genes were increased by the high concentration of estradiol, suggesting that estradiol can promote the formation of biofilm by not only positive but also negative regulations. High estradiol levels increased bacterial infection rate in organs, biofilm formation and capsular contracture. Further, high estradiol caused a large number of inflammatory cells to infiltrate and caused serious inflammatory reactions that aggravate the immune imbalances of the host. CONCLUSION High estradiol levels contribute to increasing capsular contracture caused by S. epidermidis biofilm formation. NO LEVEL ASSIGNED This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.
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XX sex chromosome complement promotes atherosclerosis in mice. Nat Commun 2019; 10:2631. [PMID: 31201301 PMCID: PMC6643208 DOI: 10.1038/s41467-019-10462-z] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Accepted: 05/08/2019] [Indexed: 12/27/2022] Open
Abstract
Men and women differ in circulating lipids and coronary artery disease (CAD). While sex hormones such as estrogens decrease CAD risk, hormone replacement therapy increases risk. Biological sex is determined by sex hormones and chromosomes, but effects of sex chromosomes on circulating lipids and atherosclerosis are unknown. Here, we use mouse models to separate effects of sex chromosomes and hormones on atherosclerosis, circulating lipids and intestinal fat metabolism. We assess atherosclerosis in multiple models and experimental paradigms that distinguish effects of sex chromosomes, and male or female gonads. Pro-atherogenic lipids and atherosclerosis are greater in XX than XY mice, indicating a primary effect of sex chromosomes. Small intestine expression of enzymes involved in lipid absorption and chylomicron assembly are greater in XX male and female mice with higher intestinal lipids. Together, our results show that an XX sex chromosome complement promotes the bioavailability of dietary fat to accelerate atherosclerosis. Men and women differ in their risk of developing coronary artery disease, in part due to differences in their levels of sex hormones. Here, AlSiraj et al. show that the XX sex genotype regulates lipid metabolism and promotes atherosclerosis independently of sex hormones in mice.
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Sasaki Y, Ikeda Y, Miyauchi T, Uchikado Y, Akasaki Y, Ohishi M. Estrogen-SIRT1 Axis Plays a Pivotal Role in Protecting Arteries Against Menopause-Induced Senescence and Atherosclerosis. J Atheroscler Thromb 2019; 27:47-59. [PMID: 31105126 PMCID: PMC6976724 DOI: 10.5551/jat.47993] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Aim: Menopause causes arterial senescence and atherosclerotic development through decrease of estrogen. Recently, histone deacetylase SIRT1 has been reported to have protective effects against arterial senescence and atherosclerosis. However, the relationship between estrogen and SIRT1 in the context of menopause-induced arterial senescence is not well understood. The present study aims to investigate whether SIRT1 is involved in the etiology of menopause-induced arterial senescence and atherosclerotic development. Methods: Twelve-week old female apolipoprotein E-knockout (ApoE-KO) mice underwent ovariectomy (OVX) or sham surgery. Results: SIRT1 expression and endothelial nitric oxide synthase (eNOS) activation in the aorta were significantly lower in OVX mice than they were in sham mice (OVX vs. sham, n = 5 per group). Senescence-associated β-galactosidase activity, protein expression of Ac-p53 and PAI-1, and aortic atherosclerosis lesions were significantly greater in OVX mice than they were in sham mice. Administration of 17β-estradiol (E2) for eight weeks to OVX mice restored aortic SIRT1 expression, activated eNOS, and retarded OVX-induced arterial senescence and atherosclerotic development (E2 vs. control, n = 5 per group). The effects of E2 on SIRT1 upregulation, anti-senescence and anti-atherosclerosis were attenuated by administration of a SIRT1 inhibitor, sirtinol. In vitro experiment using human endothelial cells demonstrated that E2 also increased SIRT1 expression and retarded oxidized low density lipoprotein-induced premature senescence, which were also abolished by sirtinol. These results suggested that estrogen modulated arterial senescence and atherosclerosis through SIRT1. Additionally a selective estrogen receptor modulator (SERM), bazedoxifene, also augmented SIRT1 and inhibited arterial senescence and atherosclerotic development (SERM vs. control, n = 3 per group). Conclusions: Downregulation of SIRT1 causes OVX-induced arterial senescence and atherosclerosis in ApoE-KO mice. Administration of estrogen or SERM enables OVX mice to restore these alterations by SIRT1 induction.
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Affiliation(s)
- Yuichi Sasaki
- Department of Cardiovascular Medicine and Hypertension, Graduate School of Medical and Dental Sciences, Kagoshima University
| | - Yoshiyuki Ikeda
- Department of Cardiovascular Medicine and Hypertension, Graduate School of Medical and Dental Sciences, Kagoshima University
| | - Takahiro Miyauchi
- Department of Cardiovascular Medicine and Hypertension, Graduate School of Medical and Dental Sciences, Kagoshima University
| | - Yoshihiro Uchikado
- Department of Cardiovascular Medicine and Hypertension, Graduate School of Medical and Dental Sciences, Kagoshima University
| | - Yuichi Akasaki
- Department of Cardiovascular Medicine and Hypertension, Graduate School of Medical and Dental Sciences, Kagoshima University
| | - Mitsuru Ohishi
- Department of Cardiovascular Medicine and Hypertension, Graduate School of Medical and Dental Sciences, Kagoshima University
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Fortini F, Vieceli Dalla Sega F, Caliceti C, Lambertini E, Pannuti A, Peiffer DS, Balla C, Rizzo P. Estrogen-mediated protection against coronary heart disease: The role of the Notch pathway. J Steroid Biochem Mol Biol 2019; 189:87-100. [PMID: 30817989 DOI: 10.1016/j.jsbmb.2019.02.008] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Revised: 02/05/2019] [Accepted: 02/20/2019] [Indexed: 12/28/2022]
Abstract
Estrogen regulates a plethora of biological processes, under physiological and pathological conditions, by affecting key pathways involved in the regulation of cell proliferation, fate, survival and metabolism. The Notch receptors are mediators of communication between adjacent cells and are key determinants of cell fate during development and in postnatal life. Crosstalk between estrogen and the Notch pathway intervenes in many processes underlying the development and maintenance of the cardiovascular system. The identification of molecular mechanisms underlying the interaction between these types of endocrine and juxtacrine signaling are leading to a deeper understanding of physiological conditions regulated by these steroid hormones and, potentially, to novel therapeutic approaches to prevent pathologies linked to reduced levels of estrogen, such as coronary heart disease, and cardiotoxicity caused by hormone therapy for estrogen-receptor-positive breast cancer.
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Affiliation(s)
| | | | - Cristiana Caliceti
- Department of Chemistry "Giacomo Ciamician", Alma Mater Studiorum-University of Bologna, Bologna, Italy
| | - Elisabetta Lambertini
- Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, Ferrara, Italy
| | - Antonio Pannuti
- University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI, USA
| | - Daniel S Peiffer
- Oncology Research Institute, Loyola University Chicago: Health Sciences Division, Maywood, Illinois, USA; Department of Microbiology and Immunology, Loyola University Chicago: Health Sciences Division, Maywood, Illinois, USA
| | - Cristina Balla
- Cardiovascular Center, University of Ferrara, Ferrara, Italy
| | - Paola Rizzo
- Maria Cecilia Hospital, GVM Care & Research, Cotignola, RA, Italy; Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy; Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
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Puglisi R, Mattia G, Carè A, Marano G, Malorni W, Matarrese P. Non-genomic Effects of Estrogen on Cell Homeostasis and Remodeling With Special Focus on Cardiac Ischemia/Reperfusion Injury. Front Endocrinol (Lausanne) 2019; 10:733. [PMID: 31708877 PMCID: PMC6823206 DOI: 10.3389/fendo.2019.00733] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Accepted: 10/10/2019] [Indexed: 12/12/2022] Open
Abstract
This review takes into consideration the main mechanisms involved in cellular remodeling following an ischemic injury, with special focus on the possible role played by non-genomic estrogen effects. Sex differences have also been considered. In fact, cardiac ischemic events induce damage to different cellular components of the heart, such as cardiomyocytes, vascular cells, endothelial cells, and cardiac fibroblasts. The ability of the cardiovascular system to counteract an ischemic insult is orchestrated by these cell types and is carried out thanks to a number of complex molecular pathways, including genomic (slow) or non-genomic (fast) effects of estrogen. These pathways are probably responsible for differences observed between the two sexes. Literature suggests that male and female hearts, and, more in general, cardiovascular system cells, show significant differences in many parameters under both physiological and pathological conditions. In particular, many experimental studies dealing with sex differences in the cardiovascular system suggest a higher ability of females to respond to environmental insults in comparison with males. For instance, as cells from females are more effective in counteracting the ischemia/reperfusion injury if compared with males, a role for estrogen in this sex disparity has been hypothesized. However, the possible involvement of estrogen-dependent non-genomic effects on the cardiovascular system is still under debate. Further experimental studies, including sex-specific studies, are needed in order to shed further light on this matter.
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Affiliation(s)
- Rossella Puglisi
- Center for Gender Specific Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Gianfranco Mattia
- Center for Gender Specific Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Alessandra Carè
- Center for Gender Specific Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Giuseppe Marano
- Center for Gender Specific Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Walter Malorni
- Center for Gender Specific Medicine, Istituto Superiore di Sanità, Rome, Italy
- School of Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Paola Matarrese
- Center for Gender Specific Medicine, Istituto Superiore di Sanità, Rome, Italy
- *Correspondence: Paola Matarrese
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Goetz TG, Mamillapalli R, Sahin C, Majidi-Zolbin M, Ge G, Mani A, Taylor HS. Addition of Estradiol to Cross-Sex Testosterone Therapy Reduces Atherosclerosis Plaque Formation in Female ApoE-/- Mice. Endocrinology 2018; 159:754-762. [PMID: 29253190 PMCID: PMC5774248 DOI: 10.1210/en.2017-00884] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2017] [Accepted: 12/08/2017] [Indexed: 12/31/2022]
Abstract
The contributions of estradiol and testosterone to atherosclerotic lesion progression are not entirely understood. Cross-sex hormone therapy (XHT) for transgender individuals dramatically alters estrogen and testosterone levels and consequently could have widespread consequences for cardiovascular health. Yet, no preclinical research has assessed atherosclerosis risk after XHT. We examined the effects of testosterone XHT after ovariectomy on atherosclerosis plaque formation in female mice and evaluated whether adding low-dose estradiol to cross-sex testosterone treatments after ovariectomy reduced lesion formation. Six-week-old female ApoE-/- C57BL/6 mice underwent ovariectomy and began treatments with testosterone, estradiol, testosterone with low-dose estradiol, or vehicle alone until euthanized at 23 weeks of age. Atherosclerosis lesion progression was measured by Oil Red O stain and confirmed histologically. We found reduced atherosclerosis in the estradiol- and combined testosterone/estradiol-treated mice compared with those treated with testosterone or vehicle only in the whole aorta (-75%), aortic arch (-80%), and thoracic aorta (-80%). Plaque size was similarly reduced in the aortic sinus. These reductions in lesion size after combined testosterone/estradiol treatment were comparable to those obtained with estrogen alone. Testosterone/estradiol combined therapy resulted in less atherosclerosis plaque formation than either vehicle or testosterone alone after ovariectomy. Testosterone/estradiol therapy was comparable to estradiol replacement alone, whereas mice treated with testosterone only fared no better than untreated controls after ovariectomy. Adding low-dose estrogen to cross-sex testosterone therapy after oophorectomy could improve cardiovascular outcomes for transgender patients. Additionally, these results contribute to understanding of the effects of estrogen and testosterone on atherosclerosis progression.
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Affiliation(s)
- Teddy G. Goetz
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut
| | - Ramanaiah Mamillapalli
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut
| | - Cagdas Sahin
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut
| | - Masoumeh Majidi-Zolbin
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut
| | - Guanghao Ge
- Yale Cardiovascular Genetics Program, Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Arya Mani
- Yale Cardiovascular Genetics Program, Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Hugh S. Taylor
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut
- Correspondence: Hugh S. Taylor, MD, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 310 Cedar Street, New Haven, Connecticut 06510. E-mail:
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Bromage DI, Pickard JMJ, Rossello X, Ziff OJ, Burke N, Yellon DM, Davidson SM. Remote ischaemic conditioning reduces infarct size in animal in vivo models of ischaemia-reperfusion injury: a systematic review and meta-analysis. Cardiovasc Res 2017; 113:288-297. [PMID: 28028069 PMCID: PMC5408955 DOI: 10.1093/cvr/cvw219] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Accepted: 09/22/2016] [Indexed: 12/15/2022] Open
Abstract
Aims The potential of remote ischaemic conditioning (RIC) to ameliorate myocardial ischaemia-reperfusion injury (IRI) remains controversial. We aimed to analyse the pre-clinical evidence base to ascertain the overall effect and variability of RIC in animal in vivo models of myocardial IRI. Furthermore, we aimed to investigate the impact of different study protocols on the protective utility of RIC in animal models and identify gaps in our understanding of this promising therapeutic strategy. Methods and results Our primary outcome measure was the difference in mean infarct size between RIC and control groups in in vivo models of myocardial IRI. A systematic review returned 31 reports, from which we made 22 controlled comparisons of remote ischaemic preconditioning (RIPreC) and 21 of remote ischaemic perconditioning and postconditioning (RIPerC/RIPostC) in a pooled random-effects meta-analysis. In total, our analysis includes data from 280 control animals and 373 animals subject to RIC. Overall, RIPreC reduced infarct size as a percentage of area at risk by 22.8% (95% CI 18.8–26.9%), when compared with untreated controls (P < 0.001). Similarly, RIPerC/RIPostC reduced infarct size by 22.2% (95% CI 17.1–25.3%; P < 0.001). Interestingly, we observed significant heterogeneity in effect size (T2 = 92.9% and I2 = 99.4%; P < 0.001) that could not be explained by any of the experimental variables analysed by meta-regression. However, few reports have systematically characterized RIC protocols, and few of the included in vivo studies satisfactorily met study quality requirements, particularly with respect to blinding and randomization. Conclusions RIC significantly reduces infarct size in in vivo models of myocardial IRI. Heterogeneity between studies could not be explained by the experimental variables tested, but studies are limited in number and lack consistency in quality and study design. There is therefore a clear need for more well-performed in vivo studies with particular emphasis on detailed characterization of RIC protocols and investigating the potential impact of gender. Finally, more studies investigating the potential benefit of RIC in larger species are required before translation to humans.
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Affiliation(s)
| | | | | | | | | | - Derek M. Yellon
- Corresponding author. Tel: +44 203 447 9591; fax: +44 203 447 9818, E-mail:
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Iqbal F, Durham WJ, Melhem A, Raslan S, Tran TT, Wright TJ, Asghar R, Fujise K, Volpi E, Sidossis L, Abate N, Sheffield-Moore M, Tuvdendorj D. Sex-dependent difference in the relationship between adipose-tissue cholesterol efflux and estradiol concentrations in young healthy humans. Int J Dev Neurosci 2017; 64:59-62. [PMID: 28709820 DOI: 10.1016/j.ijdevneu.2017.07.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Revised: 06/16/2017] [Accepted: 07/09/2017] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Impaired adipose tissue function and lower levels of high density lipoprotein cholesterol (HDL-C) have been implicated in the development of vascular dementia, and metabolic diseases such as hypertension, atherosclerosis, type 2 diabetes (T2D) and metabolic syndrome. Interestingly, both the substrate fluxes in adipose tissue and HDL-C concentration differ between men and women. Moreover, adipose tissue cholesterol efflux has been implicated in modulation of HDL-C levels. Thus, we aimed to determine if the association between serum estradiol levels and adipose tissue cholesterol efflux is sex-dependent. METHOD We evaluated the serum estradiol levels and adipose tissue cholesterol efflux in young healthy men (n=5) and women (n=3). Adipose tissue cholesterol efflux was determined using subcutaneous microdialysis probes. Linear regression analyses were used to determine the relationship between the parameters, p<0.05 was considered as statistically significant. RESULTS Our data demonstrated that serum estradiol levels directly associated with adipose tissue cholesterol efflux; however, the relationships may be sex-dependent. We discussed our results in the context of currently available data regarding sex-dependent variability in adipose tissue function and HDL-C metabolism as a potential contributor to higher rates of vascular dementia in men. Further research is required to understand the sex-dependent and -independent variabilities in adipose tissue metabolism to determine novel targets for interventions to prevent the development of vascular dementia.
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Affiliation(s)
- Fatima Iqbal
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, United States
| | - William J Durham
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, United States
| | - Ayyash Melhem
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, United States
| | - Saleem Raslan
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, United States
| | - Tony T Tran
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, United States
| | - Traver J Wright
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, United States
| | - Rabia Asghar
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, United States
| | - Ken Fujise
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, United States
| | - Elena Volpi
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, United States
| | - Labros Sidossis
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, United States
| | - Nicola Abate
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, United States
| | - Melinda Sheffield-Moore
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, United States
| | - Demidmaa Tuvdendorj
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, United States.
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Arnold AP, Cassis LA, Eghbali M, Reue K, Sandberg K. Sex Hormones and Sex Chromosomes Cause Sex Differences in the Development of Cardiovascular Diseases. Arterioscler Thromb Vasc Biol 2017; 37:746-756. [PMID: 28279969 DOI: 10.1161/atvbaha.116.307301] [Citation(s) in RCA: 215] [Impact Index Per Article: 26.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Accepted: 02/15/2017] [Indexed: 12/25/2022]
Abstract
This review summarizes recent evidence concerning hormonal and sex chromosome effects in obesity, atherosclerosis, aneurysms, ischemia/reperfusion injury, and hypertension. Cardiovascular diseases occur and progress differently in the 2 sexes, because biological factors differing between the sexes have sex-specific protective and harmful effects. By comparing the 2 sexes directly, and breaking down sex into its component parts, one can discover sex-biasing protective mechanisms that might be targeted in the clinic. Gonadal hormones, especially estrogens and androgens, have long been found to account for some sex differences in cardiovascular diseases, and molecular mechanisms mediating these effects have recently been elucidated. More recently, the inherent sexual inequalities in effects of sex chromosome genes have also been implicated as contributors in animal models of cardiovascular diseases, especially a deleterious effect of the second X chromosome found in females but not in males. Hormonal and sex chromosome mechanisms interact in the sex-specific control of certain diseases, sometimes by opposing the action of the other.
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Affiliation(s)
- Arthur P Arnold
- From the Department of Integrative Biology and Physiology, University of California, Los Angeles (A.P.A.); Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington (L.A.C.); Department of Anesthesiology (M.E.) and Department of Human Genetics (K.R.), David Geffen School of Medicine at UCLA, Los Angeles, CA; and Department of Medicine, Georgetown University Medical Center, Washington, DC (K.S.).
| | - Lisa A Cassis
- From the Department of Integrative Biology and Physiology, University of California, Los Angeles (A.P.A.); Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington (L.A.C.); Department of Anesthesiology (M.E.) and Department of Human Genetics (K.R.), David Geffen School of Medicine at UCLA, Los Angeles, CA; and Department of Medicine, Georgetown University Medical Center, Washington, DC (K.S.)
| | - Mansoureh Eghbali
- From the Department of Integrative Biology and Physiology, University of California, Los Angeles (A.P.A.); Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington (L.A.C.); Department of Anesthesiology (M.E.) and Department of Human Genetics (K.R.), David Geffen School of Medicine at UCLA, Los Angeles, CA; and Department of Medicine, Georgetown University Medical Center, Washington, DC (K.S.)
| | - Karen Reue
- From the Department of Integrative Biology and Physiology, University of California, Los Angeles (A.P.A.); Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington (L.A.C.); Department of Anesthesiology (M.E.) and Department of Human Genetics (K.R.), David Geffen School of Medicine at UCLA, Los Angeles, CA; and Department of Medicine, Georgetown University Medical Center, Washington, DC (K.S.)
| | - Kathryn Sandberg
- From the Department of Integrative Biology and Physiology, University of California, Los Angeles (A.P.A.); Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington (L.A.C.); Department of Anesthesiology (M.E.) and Department of Human Genetics (K.R.), David Geffen School of Medicine at UCLA, Los Angeles, CA; and Department of Medicine, Georgetown University Medical Center, Washington, DC (K.S.)
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Xu Z, Li Y, Huang X, Shen W, Bai J, Shen C, Zhao Y. ESR2 Genetic Variants and Combined Oral Contraceptive Use Associated with the Risk of Stroke. Arch Med Res 2017. [DOI: 10.1016/j.arcmed.2017.03.015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Bawazeer NA, Choudhry H, Zamzami MA, Abdulaal WH, Middleton B, Moselhy SS. Role of hesperetin in LDL-receptor expression in hepatoma HepG2 cells. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2016; 16:182. [PMID: 27349523 PMCID: PMC4924268 DOI: 10.1186/s12906-016-1165-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/26/2015] [Accepted: 06/15/2016] [Indexed: 11/10/2022]
Abstract
BACKGROUND High plasma concentration of low-density lipoprotein cholesterol (LDL-c) plays a significant role in the incidence of atherosclerosis and coronary heart diseases. The aim of this study was to investigate the mechanism by which the citrus flavonoid, hesperetin, regulates the LDL receptor (LDLr) gene in the human liver using the human hepatoma cell line, HepG2. METHODS Luciferase reporter gene assays were performed (in the absence of lipoprotein) to measure the activity of the LDLr promoter and the promoters of the sterol regulatory element binding protein (SREBP) transcription factors that control the LDLr promoter. RESULTS Only SREBP-1 promoter activity was significantly increased 4 h after exposure to 200 μM hesperetin. However, after 24 h incubation with 200 μM hesperetin, the activities of all the promoter-constructs, SREBP-1a, -1c, -2 and LDLr, were significantly increased. The effects of 200 μM hesperetin on elevating LDLr mRNA levels were possibly due to regulation of LDLr gene transcription by SREBP-la and SREBP-2. CONCLUSIONS We conclude that 200 μM hesperetin was likely to have stimulated LDLr gene expression in human hepatoma HepG2 cells via increased phosphorylation of PI3K andERK1/2, which increased SREBP-1a and SREBP-2 mRNA levels and enhanced the maturation of the encoded proteins. This may lead to lower plasma LDL cholesterol; therefore, diets supplemented with hesperidin might provide cardio-protective effects and reduce mortality and morbidity from coronary heart diseases.
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Affiliation(s)
- Nora A Bawazeer
- Department of Home Economics, Taif University, Taif, Saudi Arabia
| | - Hani Choudhry
- Department of Biochemistry, Faculty of Science, Cancer and mutagensis unit, Center of Innovation in Personalized Medicine, King Fahd Center for medical Research, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mazin A Zamzami
- Department of Biochemistry, Cancer and mutagensis Unit, King Fahad Medical Research Center, KingAbdulaziz University, Jeddah, Saudi Arabia
| | - Wesam H Abdulaal
- Department of Biochemistry, Cancer and mutagensis Unit, King Fahad Medical Research Center, KingAbdulaziz University, Jeddah, Saudi Arabia
| | - Bruce Middleton
- Department of Biochemistry, Medical School, Nottingham University, Nottingham, UK
| | - Said S Moselhy
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia.
- Department of Biochemistry, Faculty of Science, Ain shams University, Cairo, Egypt.
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Umetani M. Re-adopting classical nuclear receptors by cholesterol metabolites. J Steroid Biochem Mol Biol 2016; 157:20-6. [PMID: 26563834 PMCID: PMC4724260 DOI: 10.1016/j.jsbmb.2015.11.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2015] [Revised: 07/10/2015] [Accepted: 11/04/2015] [Indexed: 12/22/2022]
Abstract
Since the first cloning of the human estrogen receptor (ER) α in 1986 and the subsequent cloning of human ERβ, there has been extensive investigation of the role of estrogen/ER. Estrogens/ER play important roles not only in sexual development and reproduction but also in a variety of other functions in multiple tissues. Selective Estrogen Receptor Modulators (SERMs) are ER lignds that act as agonists or antagonists depending on the target genes and tissues, and until recently, only synthetic SERMs have been recognized. However, the discovery of the first endogenous SERM, 27-hydroxycholesterol (27HC), opened a new dimension of ER action in health and disease. In addition to the identification of 27HC as a SERM, oxysterols have been recently demonstrated as indirect modulators of ER through interaction with the nuclear receptor Liver X Receptor (LXR) β. In this review, the recent progress on these novel roles of oxysterols in ER modulation is summarized.
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Affiliation(s)
- Michihisa Umetani
- Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, 3517 Cullen Blvd, SERC 545, Houston, TX 77204-5056, USA.
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Impact of estrogens on atherosclerosis and bone in the apolipoprotein E-deficient mouse model. Menopause 2016; 22:428-36. [PMID: 25203894 DOI: 10.1097/gme.0000000000000328] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE The common inflammatory pathophysiology has nourished the hypothesis of a relationship between osteoporosis and cardiovascular disease. Estrogens are key agents in the modulation of both processes. We investigated whether induction of atherosclerosis affects bone and whether estrogens modulate both processes. METHODS Female apolipoprotein E-deficient mice (a well-established model of atherogenesis) were ovariectomized or falsely operated and fed either standard diet or high-fat diet (HFD). Six animals were included in each of the four groups. To clarify mechanisms, we treated preosteoblastic MC3T3-E1 cells with mouse serum. RESULTS Physiological levels of estrogens in falsely operated mice limited atherosclerotic burden in the thoracic aorta, but not in the aortic arch. Bone resorption, as assessed by C-telopeptides, was increased by ovariectomy in animals fed standard diet, but not in animals fed HFD. Bone microstructural properties at the distal femur showed deteriorated trabecular architecture in bone volumetric fraction and trabecular number after ovariectomy, but trabecular pattern factor, trabecular thickness, trabecular spacing, or the structural model index remained unchanged. Changes in cortical parameters were not significant. Volumetric bone mineral density was reduced in trabecular bone, but not in cortical bone, in ovariectomized mice fed standard diet. Preosteoblastic MC3T3-E1 cells exhibited increased cellular proliferation and viability and alkaline phosphatase activity after treatment with sera from animals fed HFD. CONCLUSIONS Endogenous estrogens partially reduce atherogenic burden in female apolipoprotein E-deficient mice. Ovariectomy increases bone resorption, but not under exacerbated proatherogenic conditions induced by HFD. The absence of apolipoprotein E might have an influence on the asymmetric responses of atherogenesis and bone resorption.
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Eschenko ND, Putilina FE, Galkina OV, Vilkova VA, Zacharova LI, Fidarov AF, Morozkina SN, Shavva AG. [Study of osteoprotective and hypolipidemic effects of estrogen 8α-analogues]. BIOMEDIT︠S︡INSKAI︠A︡ KHIMII︠A︡ 2015; 61:724-30. [PMID: 26716744 DOI: 10.18097/pbmc20156106724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The aim of this work was to study the ability of some estrogen 8α-analogues, that have CH3-group in the C-3 position, exhibit osteoprotective and cholesterolemic effects. The properties of these analogues was comparisoned with effects of native estradiol and 17α-ethynylestradiol (EE). We showed that compounds 3 ((d,l)-17β-acethoxy-3-methoxy-8α-estra-1,3,5(10)-triene) and 4 ((d,l)-3-methoxy-8α-estra-1,3,5(10)-triene-17-one) had the same osteoprotective and cholesterolemic effects as EE. The utherotropic effects of compound 3 and EE were the same, while the utherotropic activity of 17-keto derivative (compound 4) was higher than effect of EE. The osteoprotective and cholesterolemic effects of compounds 5 and 6 (d- or l-17β-acethoxy-3-methoxy-13-ethyl-8α-gone-1,3,5(10)-triene) were approximately the same, however the utherotropic action of these compounds was different: the compound 5 had significantly lower activity, but the compound 6 had the same effect in comparison with EE. Thus, all studied estrogen 8α-analogues may be used as basic constructions for structural modifications which is necessary as medications with while spectrum of biological properties.
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Affiliation(s)
- N D Eschenko
- Faculty of Biology and Chemistry Faculty, St.-Petersburg State University, St.-Petersburg, Russia
| | - F E Putilina
- Faculty of Biology and Chemistry Faculty, St.-Petersburg State University, St.-Petersburg, Russia
| | - O V Galkina
- Faculty of Biology and Chemistry Faculty, St.-Petersburg State University, St.-Petersburg, Russia
| | - V A Vilkova
- Faculty of Biology and Chemistry Faculty, St.-Petersburg State University, St.-Petersburg, Russia
| | - L I Zacharova
- Faculty of Biology and Chemistry Faculty, St.-Petersburg State University, St.-Petersburg, Russia
| | - A F Fidarov
- Faculty of Biology and Chemistry Faculty, St.-Petersburg State University, St.-Petersburg, Russia
| | - S N Morozkina
- Faculty of Biology and Chemistry Faculty, St.-Petersburg State University, St.-Petersburg, Russia
| | - A G Shavva
- Faculty of Biology and Chemistry Faculty, St.-Petersburg State University, St.-Petersburg, Russia
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Prossnitz ER, Hathaway HJ. What have we learned about GPER function in physiology and disease from knockout mice? J Steroid Biochem Mol Biol 2015; 153:114-26. [PMID: 26189910 PMCID: PMC4568147 DOI: 10.1016/j.jsbmb.2015.06.014] [Citation(s) in RCA: 113] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Revised: 06/24/2015] [Accepted: 06/25/2015] [Indexed: 12/16/2022]
Abstract
Estrogens, predominantly 17β-estradiol, exert diverse effects throughout the body in both normal and pathophysiology, during development and in reproductive, metabolic, endocrine, cardiovascular, nervous, musculoskeletal and immune systems. Estrogen and its receptors also play important roles in carcinogenesis and therapy, particularly for breast cancer. In addition to the classical nuclear estrogen receptors (ERα and ERβ) that traditionally mediate predominantly genomic signaling, the G protein-coupled estrogen receptor GPER has become recognized as a critical mediator of rapid signaling in response to estrogen. Mouse models, and in particular knockout (KO) mice, represent an important approach to understand the functions of receptors in normal physiology and disease. Whereas ERα KO mice display multiple significant defects in reproduction and mammary gland development, ERβ KO phenotypes are more limited, and GPER KO exhibit no reproductive deficits. However, the study of GPER KO mice over the last six years has revealed that GPER deficiency results in multiple physiological alterations including obesity, cardiovascular dysfunction, insulin resistance and glucose intolerance. In addition, the lack of estrogen-mediated effects in numerous tissues of GPER KO mice, studied in vivo or ex vivo, including those of the cardiovascular, endocrine, nervous and immune systems, reveals GPER as a genuine mediator of estrogen action. Importantly, GPER KO mice have also demonstrated roles for GPER in breast carcinogenesis and metastasis. In combination with the supporting effects of GPER-selective ligands and GPER knockdown approaches, GPER KO mice demonstrate the therapeutic potential of targeting GPER activity in diseases as diverse as obesity, diabetes, multiple sclerosis, hypertension, atherosclerosis, myocardial infarction, stroke and cancer.
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Affiliation(s)
- Eric R Prossnitz
- Department of Internal Medicine, University of New Mexico, Albuquerque, NM 87131, United States; University of New Mexico Cancer Center, Albuquerque, NM 87131, United States.
| | - Helen J Hathaway
- Department of Cell Biology & Physiology, University of New Mexico, Albuquerque, NM 87131, United States; University of New Mexico Cancer Center, Albuquerque, NM 87131, United States.
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Barrett Mueller K, Lu Q, Mohammad NN, Luu V, McCurley A, Williams GH, Adler GK, Karas RH, Jaffe IZ. Estrogen receptor inhibits mineralocorticoid receptor transcriptional regulatory function. Endocrinology 2014; 155:4461-72. [PMID: 25051445 PMCID: PMC4197987 DOI: 10.1210/en.2014-1270] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The steroid hormone aldosterone (aldo) contributes to cardiovascular disease in animal models and in humans. Aldo activates the mineralocorticoid receptor (MR), a hormone-activated transcription factor, and indeed, pharmacological MR inhibition improves cardiovascular outcomes. Because the incidence of cardiovascular disease is lower in premenopausal women, we hypothesized that estrogen (E2) signaling through the estrogen receptor (ER) may protect the vasculature by inhibiting the detrimental effects of aldo signaling through the MR. We demonstrate that E2-activated ER inhibits MR-mediated gene transcription from the mouse mammary tumor virus reporter in human embryonic kidney-293 cells. In contrast, aldo-activated MR does not affect ER-mediated gene transcription. The ERα N terminus (amino acids 1-253) containing part of the DNA-binding domain is sufficient to inhibit MR genomic function, although point mutations reveal that DNA binding, ligand-independent activation, and rapid nongenomic ERα signaling are not required for this effect. Furthermore, ERα and MR are part of a complex in cell lysates, with amino acids 1-233 of the ERα N terminus being sufficient to complex with the MR. Overall, the ability of ERα to inhibit MR-mediated gene transcription correlates with the ability of ERα segments to both localize to the nucleus and complex with the MR. In cultured vascular endothelial cells expressing ERα, E2 inhibits aldo induction of the vascular MR target gene intercellular adhesion molecule-1 (ICAM-1). ICAM-1 induction by endothelial MR is known to promote vascular inflammation that could contribute to the mechanism of aldo-induced atherosclerosis. E2 also inhibits aldo induction of ICAM-1 protein and prevents aldo-enhanced leukocyte adhesion to endothelial cells. These studies support a new model in which E2-activated ER in endothelial cells forms a complex with MR in the nucleus to modulate MR regulation of the proinflammatory gene ICAM-1. Estrogen inhibition of MR regulation of genes that contribute to cardiovascular disease may be a new mechanism by which premenopausal women are protected from cardiovascular disease.
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Affiliation(s)
- Katelee Barrett Mueller
- Molecular Cardiology Research Institute (K.B.M., Q.L., N.N.M., V.L., A.M., R.H.K., I.Z.J.), Tufts Medical Center, and Sackler School of Biomedical Graduate Studies (K.B.M., R.H.K., I.Z.J.), Tufts University School of Medicine, Boston, Massachusetts 02111; and Division of Endocrinology, Diabetes, and Hypertension (G.H.W., G.K.A.), Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115
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Morozkina SN, Fidarov AF, Selivanov SI, Shavva AG. New 2-fluoro 8α-analogs of steroidal estrogens. RUSSIAN JOURNAL OF ORGANIC CHEMISTRY 2014. [DOI: 10.1134/s1070428014100182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Fernández-Pérez L, Santana-Farré R, de Mirecki-Garrido M, García I, Guerra B, Mateo-Díaz C, Iglesias-Gato D, Díaz-Chico JC, Flores-Morales A, Díaz M. Lipid profiling and transcriptomic analysis reveals a functional interplay between estradiol and growth hormone in liver. PLoS One 2014; 9:e96305. [PMID: 24816529 PMCID: PMC4015979 DOI: 10.1371/journal.pone.0096305] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2013] [Accepted: 04/05/2014] [Indexed: 01/21/2023] Open
Abstract
17β-estradiol (E2) may interfere with endocrine, metabolic, and gender-differentiated functions in liver in both females and males. Indirect mechanisms play a crucial role because of the E2 influence on the pituitary GH secretion and the GHR-JAK2-STAT5 signaling pathway in the target tissues. E2, through its interaction with the estrogen receptor, exerts direct effects on liver. Hypothyroidism also affects endocrine and metabolic functions of the liver, rendering a metabolic phenotype with features that mimic deficiencies in E2 or GH. In this work, we combined the lipid and transcriptomic analysis to obtain comprehensive information on the molecular mechanisms of E2 effects, alone and in combination with GH, to regulate liver functions in males. We used the adult hypothyroid-orchidectomized rat model to minimize the influence of internal hormones on E2 treatment and to explore its role in male-differentiated functions. E2 influenced genes involved in metabolism of lipids and endo-xenobiotics, and the GH-regulated endocrine, metabolic, immune, and male-specific responses. E2 induced a female-pattern of gene expression and inhibited GH-regulated STAT5b targeted genes. E2 did not prevent the inhibitory effects of GH on urea and amino acid metabolism-related genes. The combination of E2 and GH decreased transcriptional immune responses. E2 decreased the hepatic content of saturated fatty acids and induced a transcriptional program that seems to be mediated by the activation of PPARα. In contrast, GH inhibited fatty acid oxidation. Both E2 and GH replacements reduced hepatic CHO levels and increased the formation of cholesterol esters and triacylglycerols. Notably, the hepatic lipid profiles were endowed with singular fingerprints that may be used to segregate the effects of different hormonal replacements. In summary, we provide in vivo evidence that E2 has a significant impact on lipid content and transcriptome in male liver and that E2 exerts a marked influence on GH physiology, with implications in human therapy.
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Affiliation(s)
- Leandro Fernández-Pérez
- Department of Clinical Sciences, University of Las Palmas de Gran Canaria - Biomedical and Health Research Institute (IUIBS), Molecular and Translational Endocrinology Group, Las Palmas de Gran Canaria, Spain
- Cancer Research Institute of The Canary Islands (ICIC), Las Palmas de Gran Canaria, Canary Islands, Spain
- * E-mail:
| | - Ruymán Santana-Farré
- Department of Clinical Sciences, University of Las Palmas de Gran Canaria - Biomedical and Health Research Institute (IUIBS), Molecular and Translational Endocrinology Group, Las Palmas de Gran Canaria, Spain
| | - Mercedes de Mirecki-Garrido
- Department of Clinical Sciences, University of Las Palmas de Gran Canaria - Biomedical and Health Research Institute (IUIBS), Molecular and Translational Endocrinology Group, Las Palmas de Gran Canaria, Spain
| | - Irma García
- Cancer Research Institute of The Canary Islands (ICIC), Las Palmas de Gran Canaria, Canary Islands, Spain
- Department of Animal Biology, University of La Laguna, Laboratory of Membrane Physiology and Biophysics, La Laguna, Spain
| | - Borja Guerra
- Department of Clinical Sciences, University of Las Palmas de Gran Canaria - Biomedical and Health Research Institute (IUIBS), Molecular and Translational Endocrinology Group, Las Palmas de Gran Canaria, Spain
- Cancer Research Institute of The Canary Islands (ICIC), Las Palmas de Gran Canaria, Canary Islands, Spain
| | - Carlos Mateo-Díaz
- Department of Clinical Sciences, University of Las Palmas de Gran Canaria - Biomedical and Health Research Institute (IUIBS), Molecular and Translational Endocrinology Group, Las Palmas de Gran Canaria, Spain
- Cancer Research Institute of The Canary Islands (ICIC), Las Palmas de Gran Canaria, Canary Islands, Spain
| | - Diego Iglesias-Gato
- Molecular Endocrinology group, University of Copenhagen - Novo Nordisk Center for Protein Research, Copenhagen, Denmark
| | - Juan Carlos Díaz-Chico
- Department of Clinical Sciences, University of Las Palmas de Gran Canaria - Biomedical and Health Research Institute (IUIBS), Molecular and Translational Endocrinology Group, Las Palmas de Gran Canaria, Spain
- Cancer Research Institute of The Canary Islands (ICIC), Las Palmas de Gran Canaria, Canary Islands, Spain
| | - Amilcar Flores-Morales
- Molecular Endocrinology group, University of Copenhagen - Novo Nordisk Center for Protein Research, Copenhagen, Denmark
| | - Mario Díaz
- Cancer Research Institute of The Canary Islands (ICIC), Las Palmas de Gran Canaria, Canary Islands, Spain
- Department of Animal Biology, University of La Laguna, Laboratory of Membrane Physiology and Biophysics, La Laguna, Spain
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WANG HUAN, LIU YAN, ZHU LING, WANG WENJING, WAN ZHAOFEI, CHEN FANGYUAN, WU YAN, ZHOU JUAN, YUAN ZUYI. 17β-estradiol promotes cholesterol efflux from vascular smooth muscle cells through a liver X receptor α-dependent pathway. Int J Mol Med 2014; 33:550-8. [DOI: 10.3892/ijmm.2014.1619] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2013] [Accepted: 12/23/2013] [Indexed: 11/05/2022] Open
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Gao S, Geng YJ. LOX-1: A male hormone-regulated scavenger receptor for atherosclerosis. Vascul Pharmacol 2013; 59:138-43. [DOI: 10.1016/j.vph.2013.10.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2013] [Revised: 10/08/2013] [Accepted: 10/12/2013] [Indexed: 01/16/2023]
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Anti-inflammatory effects of a Chinese herbal medicine in atherosclerosis via estrogen receptor β mediating nitric oxide production and NF-κB suppression in endothelial cells. Cell Death Dis 2013; 4:e551. [PMID: 23519120 PMCID: PMC3615733 DOI: 10.1038/cddis.2013.66] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Bu-Shen-Ning-Xin Decoction (BSNXD) administration has alleviated the early pathologic damage of atherosclerosis by inhibiting the adhesion molecule expression and upregulating the estrogen receptor (ER) β expression in endothelial cells, and increasing the serum nitric oxide (NO) level without any effect on serum lipid status, endometrium and fat deposition in liver in ovariectomized rabbits. The BSNXD-derived serum increases ER β expression in the human umbilical vein endothelial cells (HUVECs), and decreases malondialdehyde (MDA) production, and upregulates eNOS expression then increases NO synthesis through ERβ-dependent pathway. NO not only suppresses the LPS-induced NF-κB transcription in HUVECs, but also decreases apoptosis of endothelial cells. The BSNXD-derived serum decreases monocyte chemoattractant protein-1 production, and suppresses cell adhesion molecules (ICAM-1, VCAM-1 and E-selectin) expression in HUVECs injured by oxidized low-density lipoproteins (ox-LDL), and these effects can be abolished by ERβ antagonist (R,RTHC) and NO synthase inhibitor (L-NAME). The BSNXD-derived serum-treated HUVECs supernatant reduces CCR2, LFA-1 and VLA-4 expression in monocytes cell line U937 cells, which in turn inhibits adherence of U937 to injured endothelial cells. NO synthesis increases, and MDA production decreases through ERβ-mediated pathway that suppresses apoptosis and NF-κB activity in endothelial cells that downregulates adhesion molecules expression on endothelial cells via ERβ/NO/NF-κB pathway, and in turn leukocyte adhesion, which suggests BSNXD potential value in prophylaxis atherosclerosis.
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Endogenous androgen deficiency enhances diet-induced hypercholesterolemia and atherosclerosis in low-density lipoprotein receptor-deficient mice. ACTA ACUST UNITED AC 2012; 9:319-28. [PMID: 22981166 DOI: 10.1016/j.genm.2012.08.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2012] [Revised: 08/07/2012] [Accepted: 08/22/2012] [Indexed: 01/14/2023]
Abstract
BACKGROUND Despite numerous clinical and animal studies, the role of sex steroid hormones on lipoprotein metabolism and atherosclerosis remain controversial. OBJECTIVE We sought to determine the effects of endogenous estrogen and testosterone on lipoprotein levels and atherosclerosis using mice fed a low-fat diet with no added cholesterol. METHODS Male and female low-density lipoprotein receptor-deficient mice were fed an open stock low-fat diet (10% of kcals from fat) for 2, 4, or 17 weeks. Ovariectomy, orchidectomy, or sham surgeries were performed to evaluate the effects of the presence or absence of endogenous hormones on lipid levels, lipoprotein distribution, and atherosclerosis development. RESULTS Female mice fed the study diet for 17 weeks had a marked increase in levels of total cholesterol, triglycerides, apolipoprotein-B containing lipoproteins, and atherosclerosis compared with male mice. Surprisingly, ovariectomy in female mice had no effect on any of these parameters. In contrast, castration of male mice markedly increased total cholesterol concentrations, triglycerides, apolipoprotein B-containing lipoproteins, and atherosclerotic lesion formation compared with male and female mice. CONCLUSIONS These data suggest that endogenous androgens protect against diet-induced increases in cholesterol concentrations, formation of proatherogenic lipoproteins, and atherosclerotic lesions formation. Conversely orchidectomy, which decreases androgen concentrations, promotes increases in cholesterol concentrations, proatherogenic lipoprotein formation, and atherosclerotic lesion formation in low-density lipoprotein receptor-deficient mice in response to a low-fat diet.
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29
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Tiyerili V, Müller CF, Fung S, Panek D, Nickenig G, Becher UM. Estrogen improves vascular function via peroxisome-proliferator-activated-receptor-γ. J Mol Cell Cardiol 2012; 53:268-76. [DOI: 10.1016/j.yjmcc.2012.05.008] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2012] [Revised: 05/04/2012] [Accepted: 05/12/2012] [Indexed: 12/24/2022]
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30
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Rodriguez-Leyva D, Malik A, Tappia PS. Gender-related gene expression in response to dietary fatty acids and predisposition to atherosclerosis and cardiovascular disease. ACTA ACUST UNITED AC 2011. [DOI: 10.2217/clp.11.62] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
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31
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Ali MM, Arumugam SBA. Effect of crude extract of Bombyx mori coccoons in hyperlipidemia and atherosclerosis. J Ayurveda Integr Med 2011; 2:72-8. [PMID: 21760692 PMCID: PMC3131775 DOI: 10.4103/0975-9476.82527] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2010] [Revised: 03/29/2011] [Accepted: 04/06/2011] [Indexed: 11/18/2022] Open
Abstract
The silkworm is the larva or caterpillar of the domesticated silkmoth, Bombyx mori and being a primary producer of silk is an economically important insect. These days the silk is emerging as a resource for solving a broad range of biological problems. The silk (Abresham) is popularly known as Abresham muqriz (muqriz means cut) in Unani medicine. Its cocoons are extensively used as an ingredient of various Unani formulations like Khameer-E- Abresham Sada, Khameere Abresham Hakeem Arshad Wala, Khameere Abresham Ood Mastagi Wala etc. and are used to treat many cardiac and nervous disorders. The hypolipidemic activity of this drug, along with Nepata Hindostana (Badranjboya) and Terminalia Arjuna (Arjan) has been documented. But action of extract of Bombyx mori cocoons as a single drug is not documented. That's why; it was decided to study its effect on hyperlipidemia and atherosclerosis. The Male New Zealand White rabbits all of 1.5kgs were selected for the study. After stabilization period (2 weeks) the rabbits were divided into 3 groups (Group I - Control, Group II Lesion Control and Group III treated with extract of Bombyx mori silk cocoon). Hyperlipidemia and atherosclerosis were induced with 1% cholesterol diet. After induction of hyperlipidemia and atherosclerosis for twelve weeks, Group III rabbits were treated with Bombyx mori for 6 weeks (45 days). A significant decrease in hyperlipidemia was seen within 4 weeks of treatment. Histopathologically, the atherosclerotic plaques showed reduction in size. The third group showed a significant increase in the body weight and also an increase in the HDL cholesterol levels. The study concludes that extract of Bombyx mori cocoons has a significant effect on hypercholesterolemia and atherosclerosis probably because of its antioxidant and hypolipidemic effect.
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Affiliation(s)
- Mir Mahdi Ali
- International Centre for Cardiothoracic and Vascular diseases, Frontier Lifeline Hospitals, Chennai, India
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Attenuation of Atherogenesis via the Anti-inflammatory Effects of the Selective Estrogen Receptor Beta Modulator 8β-VE2. J Cardiovasc Pharmacol 2011; 58:399-405. [DOI: 10.1097/fjc.0b013e318226bd16] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Wu Q, Chambliss K, Umetani M, Mineo C, Shaul PW. Non-nuclear estrogen receptor signaling in the endothelium. J Biol Chem 2011; 286:14737-43. [PMID: 21343284 PMCID: PMC3083154 DOI: 10.1074/jbc.r110.191791] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
In addition to the classical function of estrogen receptors (ER) as transcription factors, evidence continues to accumulate that they mediate non-nuclear processes in numerous cell types, including the endothelium, in which they activate endothelial NO synthase. Non-nuclear ER signaling entails unique post-translational modifications and protein-protein interactions of the receptor with adaptor molecules, kinases, and G proteins. Recent in vitro and in vivo studies in mice using an estrogen-dendrimer conjugate that is excluded from the nucleus indicate that non-nuclear ER activation underlies the migration and growth responses of endothelial cells to estrogen but not the growth responses of endometrial or breast cancer cells to the hormone. In this minireview, the features of ERα and protein-protein interactions that enable it to invoke extranuclear signaling in the endothelium and the consequences of that signaling are discussed.
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Affiliation(s)
- Qian Wu
- From the Division of Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390
| | - Ken Chambliss
- From the Division of Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390
| | - Michihisa Umetani
- From the Division of Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390
| | - Chieko Mineo
- From the Division of Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390
| | - Philip W. Shaul
- From the Division of Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390
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Umetani M, Shaul PW. 27-Hydroxycholesterol: the first identified endogenous SERM. Trends Endocrinol Metab 2011; 22:130-5. [PMID: 21353593 PMCID: PMC3070823 DOI: 10.1016/j.tem.2011.01.003] [Citation(s) in RCA: 88] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2010] [Revised: 01/15/2011] [Accepted: 01/18/2011] [Indexed: 12/12/2022]
Abstract
The cholesterol metabolite 27-hydroxycholesterol (27OHC) classically delivers sterols from peripheral tissues to the liver and is a substrate for bile acid synthesis. Recent studies have revealed that 27OHC also binds to and modifies the function of estrogen receptors ERα and ERβ. Experiments in mice lacking the enzyme which synthesizes 27OHC, CYP27A1, or the enzyme which catabolizes 27OHC, CYP7B1, have demonstrated that 27OHC adversely affects estrogen-related cardiovascular protection and bone mineralization. Work in breast cancer cells further indicates that 27OHC alters ER target gene expression to promote cell growth. Therefore, 27OHC is the first identified endogenous selective estrogen receptor modulator (SERM) and could have an important impact upon the cardiovascular system, bone biology, and cancer.
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Affiliation(s)
- Michihisa Umetani
- Division of Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX USA
- Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX USA
| | - Philip W. Shaul
- Division of Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX USA
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35
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Lenfant F, Trémollières F, Gourdy P, Arnal JF. Timing of the vascular actions of estrogens in experimental and human studies: why protective early, and not when delayed? Maturitas 2010; 68:165-73. [PMID: 21167666 DOI: 10.1016/j.maturitas.2010.11.016] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2010] [Revised: 11/18/2010] [Accepted: 11/18/2010] [Indexed: 01/27/2023]
Abstract
Estrogens, and in particular 17β-estradiol (E2), play a pivotal role in sexual development and reproduction and are also implicated in a large number of physiological processes including the cardiovascular system. Although epidemiological studies and Nurses' Health Study suggested, and all animal models of early atheroma clearly demonstrated a vasculoprotective action of both endogenous and exogenous estrogens, the Women's Health Initiative did not confirm the preventive action of estrogens against coronary heart disease (CHD). However, women who initiated hormone therapy closer to menopause tended to have reduced CHD risk compared with increased CHD risk among women more distant from menopause. Thus, it is now mandatory to try to understand the mechanisms that could have influenced the actions of estrogens at various stages of atherosclerosis and/or of life. In this current review, we will summarize our understanding of the potential cellular targets and mechanisms of the vasculoprotective actions of estrogens, as well as of the lack of action of estrogens when administered after a period of hormonal deprivation. The mechanisms of the aggravating role of progestogens such as medroxyprogesterone acetate will be considered. Finally, we will analyze the possibilities to uncouple some beneficial from other undesirable actions following the partial/selective activation of estrogen receptors.
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Affiliation(s)
- Françoise Lenfant
- INSERM U1048-I2MC, Faculté de Médecine, Université de Toulouse III et CHU de Toulouse, Toulouse, France.
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36
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Nilsson S, Gustafsson JÅ. Estrogen receptors: therapies targeted to receptor subtypes. Clin Pharmacol Ther 2010; 89:44-55. [PMID: 21124311 DOI: 10.1038/clpt.2010.226] [Citation(s) in RCA: 253] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Over the past two decades, we have learned that estrogens play important physiological roles not only in women but also in men and that the biological effects of estrogen are mediated by not one but two distinct estrogen receptors (ERs), ERα and ERβ. Our appreciation of the physiological importance of estrogen and the mechanisms by which it acts has significantly increased over the years; however, we are only now beginning to decipher the roles of ERα and ERβ in different organs and to elucidate how selective ligands, acting through either of the two ERs, can prevent or treat various age- or sex-specific diseases. The specific roles of ERα and ERβ and the therapeutic potential of ER subtype-selective agonists in bone and metabolic homeostasis, depression, vasomotor symptoms, neurodegenerative diseases, and cancer are reviewed herein. It must be stated, however, that appropriate clinical studies are necessary to validate these compounds as agents for the prevention and treatment of diseases.
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Affiliation(s)
- S Nilsson
- Karo Bio AB, Novum, Huddinge, Sweden
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Bourghardt J, Wilhelmson ASK, Alexanderson C, De Gendt K, Verhoeven G, Krettek A, Ohlsson C, Tivesten A. Androgen receptor-dependent and independent atheroprotection by testosterone in male mice. Endocrinology 2010; 151:5428-37. [PMID: 20861231 DOI: 10.1210/en.2010-0663] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The atheroprotective effect of testosterone is thought to require aromatization of testosterone to estradiol, but no study has adequately addressed the role of the androgen receptor (AR), the major pathway for the physiological effects of testosterone. We used AR knockout (ARKO) mice on apolipoprotein E-deficient background to study the role of the AR in testosterone atheroprotection in male mice. Because ARKO mice are testosterone deficient, we sham operated or orchiectomized (Orx) the mice before puberty, and Orx mice were supplemented with placebo or a physiological testosterone dose. From 8 to 16 wk of age, the mice consumed a high-fat diet. In the aortic root, ARKO mice showed increased atherosclerotic lesion area (+80%, P < 0.05). Compared with placebo, testosterone reduced lesion area both in Orx wild-type (WT) mice (by 50%, P < 0.001) and ARKO mice (by 24%, P < 0.05). However, lesion area was larger in testosterone-supplemented ARKO compared with testosterone-supplemented WT mice (+57%, P < 0.05). In WT mice, testosterone reduced the presence of a necrotic core in the plaque (80% among placebo-treated vs. 12% among testosterone-treated mice; P < 0.05), whereas there was no significant effect in ARKO mice (P = 0.20). In conclusion, ARKO mice on apolipoprotein E-deficient background display accelerated atherosclerosis. Testosterone treatment reduced atherosclerosis in both WT and ARKO mice. However, the effect on lesion area and complexity was more pronounced in WT than in ARKO mice, and lesion area was larger in ARKO mice even after testosterone supplementation. These results are consistent with an AR-dependent as well as an AR-independent component of testosterone atheroprotection in male mice.
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Affiliation(s)
- Johan Bourghardt
- Wallenberg Laboratory for Cardiovascular Research, Bruna Stråket 16, Sahlgrenska University Hospital, SE-413 45 Gothenburg, Sweden
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Zhao C, Dahlman-Wright K, Gustafsson JÅ. Estrogen signaling via estrogen receptor {beta}. J Biol Chem 2010; 285:39575-9. [PMID: 20956532 DOI: 10.1074/jbc.r110.180109] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Estrogens act by binding to and activating two estrogen receptors (ERs), ERα and ERβ. Transcriptional regulation by ERs is controlled by a complex array of factors such as ER-ligand binding, the DNA sequence bound by ERs, ER-interacting cofactors, and chromatin context. This minireview will provide an overview of the most recent advances in the identification of ERβ-regulated target gene networks and ERβ DNA-binding sites. We also highlight the recent work establishing new roles of ERβ signaling, including protective functions in the epithelial-mesenchymal transition and in atherosclerosis, as well as regulation of cell proliferation in the colon.
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Affiliation(s)
- Chunyan Zhao
- Department of Biosciences and Nutrition, Novum, Karolinska Institutet, S-141 57 Huddinge, Sweden
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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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Kontos S, Kominea A, Melachrinou M, Balampani E, Sotiropoulou-Bonikou G. Inverse expression of estrogen receptor-β and nuclear factor-κB in urinary bladder carcinogenesis. Int J Urol 2010; 17:801-9. [DOI: 10.1111/j.1442-2042.2010.02603.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Wang L, Hao Q, Wang YD, Wang WJ, Li DJ. Protective effects of dehydroepiandrosterone on atherosclerosis in ovariectomized rabbits via alleviating inflammatory injury in endothelial cells. Atherosclerosis 2010; 214:47-57. [PMID: 21071029 DOI: 10.1016/j.atherosclerosis.2010.07.043] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2009] [Revised: 06/28/2010] [Accepted: 07/21/2010] [Indexed: 11/30/2022]
Abstract
OBJECTIVE The risk for atherosclerosis is increased in postmenopausal women. Dehydroepiandrosterone (DHEA) is postulated to have anti-atherogenic properties, but the mechanism remains unclear. The aim of this study was to elucidate the protective effect of DHEA on atherosclerosis in ovariectomized rabbits. METHODS The lipid status and atherosclerotic lesions were examined in vivo in ovariectomized rabbits. The effects of DHEA on expression of inflammatory molecules were evaluated in vitro, such as nitric oxide (NO), malondialdehyde (MDA), monocyte chemoattractant protein-1 (MCP-1), adhesion molecules (ICAM-1, VCAM-1 and E-selectin) in the human umbilical vein endothelial cells (HUVECs) injured by oxidized low-density lipoproteins (ox-LDL). The adhesion of the monocytic U937 cells to HUVECs was treated with supernatants of ox-LDL treated HUVECs with or without DHEA, and then the expressions of CCR2, LFA-1, VLA-4 were analyzed in U937 cells. The HUVECs with or without LPS treatment were then treated with DHEA, and NF-κB activity was measured by luciferase activity. RESULTS DHEA administration alleviates efficiently the early pathologic damage of atherosclerosis, increases the serum NO level, and up-regulates the endothelial cell estrogen receptor (ER) expression of ovariectomized rabbits. DHEA in vitro significantly promotes NO synthesis, suppresses MDA and MCP-1 secretion of endothelial cells, and decreases ICAM-1, VCAM-1 and E-selectin expression in HUVECs; neither selective ERα antagonist (methyl-piperidino-pyrazole, MPP) nor ERβ antagonist (R,R-tetrahydrochrysene, R,RTHC) can abolish these effects. Furthermore, DHEA reduces CCR2, LFA-1 and VLA-4 expression in U937 cells, which in turn inhibits the adherence of monocytes to the injured endothelial cells. DHEA significantly decreased the LPS-induced NF-κB transcription. CONCLUSIONS Our findings suggest that DHEA can alleviate inflammation in endothelial cells. The effects of DHEA on endothelial cells are independent of ERα or ERβ pathway, but at least in part, through suppression of NF-κB activity, which protects from atherosclerosis triggered by monocyte adherence.
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Affiliation(s)
- Ling Wang
- Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, China
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Rayner K, Chen YX, Siebert T, O'Brien ER. Heat Shock Protein 27: Clue to Understanding Estrogen-Mediated Atheroprotection? Trends Cardiovasc Med 2010; 20:54-8. [DOI: 10.1016/j.tcm.2010.03.008] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Arnal JF, Laurell H, Fontaine C, Billon A, Calippe B, Lenfant F, Gourdy P. Estrogen receptor actions on vascular biology and inflammation: implications in vascular pathophysiology. Climacteric 2010; 12 Suppl 1:12-7. [PMID: 19811234 DOI: 10.1080/13697130902820006] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Whereas hormonal therapy (HT) may increase the risk of coronary heart disease (CHD) and stroke in menopausal women, epidemiological studies (protection in premenopausal women) suggest and experimental studies (prevention of fatty streak development in animals) demonstrate a major atheroprotective action of estradiol (E2). The understanding of the deleterious and beneficial effects of estrogens is thus required at both a cellular and molecular level. Both the endothelium and the immuno-inflammatory system play a key role in the development of fatty streak deposit as well as in the rupture of the atherosclerotic plaque. Whereas E2 favors an anti-inflammatory effect in vitro (cultured cells), it rather elicits a pro-inflammatory response in vivo at the level of several subpopulations of the immuno-inflammatory system, which could contribute to plaque destabilization. E2 promotes beneficial actions on the endothelium such as nitric oxide and prostacyclin production. E2 actions are essentially mediated by two molecular targets: estrogen receptor alpha (ER-alpha) and beta (ER-beta), but the former appears to mediate most of the actions of E2 on the endothelium and on the immune system. ER-alpha modulates target gene transcription through two activation functions (AF), AF-1 and AF-2, even though signalling via ER-alpha located at the plasma membrane (responsible for membrane-initiated steroid signalling (MISS)/(extra-genomic)) can also lead to an indirect effect on gene transcription. Recently, we demonstrated that ER-alpha AF-1 is not required for the vasculoprotective actions of E2, whereas it is necessary for the effects of E2 on its reproductive targets. These results suggest that selective estrogen receptor modulators stimulating ER-alpha with minimal activation of ER-alpha AF-1 could retain beneficial vascular actions, while minimizing the sexual effects.
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Affiliation(s)
- J F Arnal
- INSERM U858-I2MR, Université de Toulouse and CHU de Toulouse, Toulouse, France
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Leibetseder V, Humpeler S, Zuckermann A, Svoboda M, Thalhammer T, Marktl W, Ekmekcioglu C. Time dependence of estrogen receptor expression in human hearts. Biomed Pharmacother 2009; 64:154-9. [PMID: 19944560 DOI: 10.1016/j.biopha.2009.09.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2009] [Accepted: 09/09/2009] [Indexed: 11/24/2022] Open
Abstract
OBJECTIVES AND AIMS Transcriptional effects of estrogens are primarily mediated by the two nuclear estrogen receptors (ER), ERalpha and ERbeta. Both receptors are present in the vasculature and in the human heart and have been shown to act antiatherogenic and to be protective against the development of cardiac hypertrophy. The aim was to quantify ER mRNA expression in left ventricular specimens from patients with coronary heart disease (CHD, n=15) and dilated cardiomyopathy (CMP, n=38) and compare their levels with those from healthy heart donors (n=9). Additionally, a possible variation of ERmRNA expression in human hearts in respect to time of day was studied. METHODS AND RESULTS mRNA expression of both ER receptors was detected by real-time PCR in all of the human specimens. There was no difference in the relative quantity of the receptors between CHD and CMP patients. However, control specimens showed significant lower levels of either receptor in the healthy myocardium (p<.001 each). Analyzing the time dependency of receptor expression with a cosinor analysis showed a significant 8-hour period rhythm for ERbeta in CMP- but no rhythm in CHD patients. Due to the low patient number, rhythmic analysis was not possible in controls. CONCLUSIONS The increased ERalpha and ERbeta mRNA expression in left ventricular specimens from CHD and CMP patients might reflect a compensatory mechanism to counteract the decline in ventricular function. Furthermore, we provided evidence for a time dependent variation of ERbeta receptor expression in the human heart.
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Affiliation(s)
- Valentin Leibetseder
- Department of Physiology, Center of Physiology and Pharmacology, Medical University Vienna, Schwarzspanierstrasse 17, Vienna, Austria
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Dubey RK, Jackson EK. Potential vascular actions of 2-methoxyestradiol. Trends Endocrinol Metab 2009; 20:374-9. [PMID: 19734053 PMCID: PMC2761235 DOI: 10.1016/j.tem.2009.04.007] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2008] [Revised: 04/03/2009] [Accepted: 04/07/2009] [Indexed: 12/29/2022]
Abstract
2-Methoxyestradiol (2-ME) is a biologically active metabolite of 17beta-estradiol that appears to inhibit key processes associated with cell replication in vitro. The molecule has been suggested to have potent growth-inhibitory effects on proliferating cells, including smooth muscle cells and endothelial cells, and may be antiangiogenic. Because of these potential roles for 2-ME, its lack of cytotoxicity and low estrogenic activity, we hypothesize that 2-ME could be a valuable therapeutic molecule for prevention and treatment of cardiovascular diseases. Whether 2-ME is as effective in vivo as it is in vitro at modulating vascular processes remains controversial. Here we discuss recent developments regarding mechanisms by which 2-ME might regulate vascular activity and angiogenesis and speculate on the therapeutic implications of these developments.
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Affiliation(s)
- Raghvendra K Dubey
- Clinic for Reproductive Endocrinology, Department of Obstetrics and Gynecology, Zurich Center for Integrative Human Physiology, University Hospital Zurich, Frauenklinikstrasse, Zurich, Switzerland.
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Abstract
Females-both rats and women-are substantially protected against the age-dependent decrease in renal function that occurs in males of the species. In part, this finding reflects the cardioprotective and renoprotective effects of estrogens, but estrogen has multiple actions, not all of which are beneficial. In addition, the low androgen level in women might be protective against a decline in renal function, but animal and clinical data on possible adverse effects of androgens are controversial. Androgens also have multiple actions, one of which-aromatization to estrogen-is likely to be protective. Sex steroids clearly have many complex actions, which explains the conflicting information on their relative benefits and dangers. Endothelial nitric oxide (NO) deficiency contributes importantly to cardiovascular risk and intrarenal NO deficiency is clearly linked to chronic kidney disease progression in animal models. Endothelial dysfunction develops with increasing age but is delayed in females, correlating with a delayed rise in asymmetric dimethylarginine level. There is no clear link between aging and arginine (the NO synthase substrate) deficiency. Animal data suggest that the aging kidney develops NO deficiency as a result of changes in neuronal NO synthase. The increased oxidative stress that occurs with aging affects multiple stages of the NO biosynthetic pathway and results in decreased production and/or action of NO. NO production is better preserved in females than in males, partly as a result of the actions of estrogens.
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Villablanca AC, Tenwolde A, Lee M, Huck M, Mumenthaler S, Rutledge JC. 17beta-estradiol prevents early-stage atherosclerosis in estrogen receptor-alpha deficient female mice. J Cardiovasc Transl Res 2009; 2:289-99. [PMID: 19654889 PMCID: PMC2719738 DOI: 10.1007/s12265-009-9103-z] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2009] [Accepted: 04/17/2009] [Indexed: 11/25/2022]
Abstract
Estrogen is atheroprotective and a high-affinity ligand for both known estrogen receptors, ERα and ERβ. However, the role of the ERα in early-stage atherosclerosis has not been directly investigated and is incompletely understood. ERα-deficient (ERα−/−) and wild-type (ERα+/+) female mice consuming an atherogenic diet were studied concurrent with estrogen replacement to distinguish the actions of 17β-estradiol (E2) from those of ERα on the development of early atherosclerotic lesions. Mice were ovariectomized and implanted with subcutaneous slow-release pellets designed to deliver 6 or 8 μg/day of exogenous 17β-estradiol (E2) for a period of up to 4 months. Ovariectomized mice (OVX) with placebo pellets (E2-deficient controls) were compared to mice with endogenous E2 (intact ovaries) and exogenous E2. Aortas were analyzed for lesion area, number, and distribution. Lipid and hormone levels were also determined. Compared to OVX, early lesion development was significantly (p < 0.001) attenuated by E2 with 55–64% reduction in lesion area by endogenous E2 and >90% reduction by exogenous E2. Compared to OVX, a decline in lesion number (2- to 4-fold) and lesser predilection (~4-fold) of lesion formation in the proximal aorta also occurred with E2. Lesion size, development, number, and distribution inversely correlated with circulating plasma E2 levels. However, atheroprotection was independent of ERα status, and E2 athero-protection in both genotypes was not explained by changes in plasma lipid levels (total cholesterol, triglyceride, and high-density lipoprotein cholesterol). The ERα is not essential for endogenous/exogenous E2-mediated protection against early-stage atherosclerosis. These observations have potentially significant implications for understanding the molecular and cellular mechanisms and timing of estrogen action in different estrogen receptor (ER) deletion murine models of atherosclerosis, as well as implications to human studies of ER polymorphisms and lipid metabolism. Our findings may contribute to future improved clinical decision-making concerning the use of hormone therapy.
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Affiliation(s)
- Amparo C Villablanca
- Department of Internal Medicine, University of California, Davis, Davis, CA, USA.
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Banerjee A, Rose R, Johnson GA, Burghardt RC, Ramaiah SK. The Influence of Estrogen on Hepatobiliary Osteopontin (SPP1) Expression in a Female Rodent Model of Alcoholic Steatohepatitis. Toxicol Pathol 2009; 37:492-501. [DOI: 10.1177/0192623309335633] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Our recent studies suggest that higher neutrophil infiltration in females correlates with increased hepatobiliary expression of osteopontin (OPN) in alcoholic steatohepatitis (ASH). The objective of this study was to understand the role of alcohol in altering estrogen levels in females by examining the effect of ethanol (EtOH) on the estrous cycle and then investigate the potential relationship between estradiol (E2) and hepatobiliary OPN expression in a female rat ASH model. Ovariectomized (OVX) and E2-implanted OVX rats in the ASH group were evaluated for OPN mRNA and protein expression. Low doses of E2 resulted in significant down-regulation of OPN protein and mRNA as compared to the OVX group. However, with increasing doses of E2, there was up-regulation of both OPN mRNA and protein. Osteopontin was localized primarily to the biliary epithelium. Liver injury assessed by serum ALT and histopathology revealed a pattern similar to OPN expression. In all groups, hepatic neutrophilic infiltration correlated positively with OPN expression. Based on these data, we conclude that in our ASH model, low doses of E2 appear to be hepatoprotective, whereas the protective effect appears to diminish with increasing doses of E2, although additional cause and effect studies are needed for confirmation.
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Affiliation(s)
- Atrayee Banerjee
- Department of Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843-4467, USA
| | - Robert Rose
- Department of Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843-4467, USA
| | - Greg A. Johnson
- Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843-4467, USA
| | - Robert C. Burghardt
- Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843-4467, USA
| | - Shashi K. Ramaiah
- Department of Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843-4467, USA
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The transactivating function 1 of estrogen receptor alpha is dispensable for the vasculoprotective actions of 17beta-estradiol. Proc Natl Acad Sci U S A 2009; 106:2053-8. [PMID: 19188600 DOI: 10.1073/pnas.0808742106] [Citation(s) in RCA: 99] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Full-length 66-kDa estrogen receptor alpha (ERalpha) stimulates target gene transcription through two activation functions (AFs), AF-1 in the N-terminal domain and AF-2 in the ligand binding domain. Another physiologically expressed 46-kDa ERalpha isoform lacks the N-terminal A/B domains and is consequently devoid of AF-1. Previous studies in cultured endothelial cells showed that the N-terminal A/B domain might not be required for estradiol (E2)-elicited NO production. To evaluate the involvement of ERalpha AF-1 in the vasculoprotective actions of E2, we generated a targeted deletion of the ERalpha A/B domain in the mouse. In these ERalphaAF-1(0) mice, both basal endothelial NO production and reendothelialization process were increased by E2 administration to a similar extent than in control mice. Furthermore, exogenous E2 similarly decreased fatty streak deposits at the aortic root from both ovariectomized 18-week-old ERalphaAF-1(+/+) LDLr(-/-) (low-density lipoprotein receptor) and ERalphaAF-1(0) LDLr (-/-) mice fed with a hypercholesterolemic diet. In addition, quantification of lesion size on en face preparations of the aortic tree of 8-month-old ovariectomized or intact female mice revealed that ERalpha AF-1 is dispensable for the atheroprotective action of endogenous estrogens. We conclude that ERalpha AF-1 is not required for three major vasculoprotective actions of E2, whereas it is necessary for the effects of E2 on its reproductive targets. Thus, selective ER modulators stimulating ERalpha with minimal activation of ERalpha AF-1 could retain beneficial vascular actions, while minimizing the sexual effects.
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Arnal JF, Gourdy P, Simoncini T. Interference of progestins with endothelial actions of estrogens: a matter of glucocorticoid action or deprivation? Arterioscler Thromb Vasc Biol 2009; 29:441-3. [PMID: 19179642 DOI: 10.1161/atvbaha.108.182337] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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