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Zhou J, Wu J, Jiang D, Cai S, Zhang C, Ying J, Cao J, Song Y, Song P. National, regional and provincial prevalence of childhood hypertension in China in 2020: a systematic review and modelling study. THE LANCET. CHILD & ADOLESCENT HEALTH 2024; 8:872-881. [PMID: 39488220 DOI: 10.1016/s2352-4642(24)00260-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 09/26/2024] [Accepted: 09/26/2024] [Indexed: 11/04/2024]
Abstract
BACKGROUND Childhood hypertension is a growing health concern in China. Accurate estimation of prevalence is essential but challenging due to the variability of blood pressure and the need for multiple occasions for confirmation. This study aimed to estimate the national, regional, and provincial prevalence of childhood hypertension in China in 2020. METHODS For this systematic review and modelling study, we did a comprehensive literature search of epidemiological studies reporting the prevalence of elevated blood pressure (EBP) or hypertension among Chinese children (aged 18 years or younger) that were published between Jan 1, 1990 and June 20, 2024 in PubMed, Embase, MEDLINE, China National Knowledge Infrastructure, Wanfang Data, and Chinese Science and Technology Journal Database. EBP was defined as blood pressure greater than or equal to the 95th percentile on a single occasion, and childhood hypertension as blood pressure greater than or equal to the 95th percentile consistently across three occasions. First, we estimated the prevalence of childhood EBP using a multi-level mixed-effects meta-regression and the pooled odds ratios (ORs) for factors associated with childhood EBP through random-effects meta-analysis. Second, the ratio of childhood EBP to childhood hypertension was calculated via random-effects meta-analysis, based on which the national and regional prevalence of childhood hypertension was imputed. Finally, we derived the provincial prevalence of childhood hypertension using an associated factor-based model. The review protocol was registered in PROSPERO (CRD42024537570). FINDINGS We identified 8872 records, of which 134 articles covering 22 431 861 children were included. In 2020, the overall prevalence of hypertension among Chinese children aged 6-18 years was 3·11% (95% CI 2·35-4·04), equivalent to 6·80 million (5·13-8·83) affected children. The prevalence of childhood hypertension ranged from 2·25% (1·54-2·75) for children aged 6 years to 2·01% (1·36-3·37) for those aged 18 years, peaking at 3·84% (2·97-4·94) for those aged 14 years. The overall prevalence was higher in boys (3·34% [2·53-4·35]) than in girls (2·85% [2·13-3·69]). Associations between four factors (overweight, obesity, salted food intake, and family history of hypertension) and childhood EBP were graded as highly suggestive evidence. INTERPRETATION This study reveals substantial regional and provincial variations in the prevalence of childhood hypertension in China. Our findings could inform targeted public health initiatives and optimise resource allocation to address this public health concern. FUNDING This study was supported by the National Natural Science Foundation of China (72104211 and 82273654) and the Chao Kuang Piu High-tech Development Fund (2022RC019). TRANSLATION For the Chinese translation of the abstract see Supplementary Materials section.
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Affiliation(s)
- Jiali Zhou
- Center for Clinical Big Data and Statistics of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; School of Public Health, Zhejiang University School of Medicine, Hangzhou, China
| | - Jing Wu
- Center for Clinical Big Data and Statistics of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; School of Public Health, Zhejiang University School of Medicine, Hangzhou, China
| | - Denan Jiang
- Center for Clinical Big Data and Statistics of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; School of Public Health, Zhejiang University School of Medicine, Hangzhou, China; International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China
| | - Shan Cai
- Institute of Child and Adolescent Health and School of Public Health, Peking University, Beijing, China; National Health Commission Key Laboratory of Reproductive Health, Beijing, China
| | - Chenhao Zhang
- Center for Clinical Big Data and Statistics of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; School of Public Health, Zhejiang University School of Medicine, Hangzhou, China
| | - Jiayao Ying
- Center for Clinical Big Data and Statistics of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; School of Public Health, Zhejiang University School of Medicine, Hangzhou, China
| | - Jin Cao
- Center for Clinical Big Data and Statistics of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; School of Public Health, Zhejiang University School of Medicine, Hangzhou, China
| | - Yi Song
- Institute of Child and Adolescent Health and School of Public Health, Peking University, Beijing, China; National Health Commission Key Laboratory of Reproductive Health, Beijing, China
| | - Peige Song
- Center for Clinical Big Data and Statistics of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; School of Public Health, Zhejiang University School of Medicine, Hangzhou, China.
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Zhou J, Sun W, Zhang C, Hou L, Luo Z, Jiang D, Tan B, Yuan C, Zhao D, Li J, Zhang R, Song P. Prevalence of childhood hypertension and associated factors in Zhejiang Province: a cross-sectional analysis based on random forest model and logistic regression. BMC Public Health 2024; 24:2101. [PMID: 39097727 PMCID: PMC11298091 DOI: 10.1186/s12889-024-19630-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Accepted: 07/29/2024] [Indexed: 08/05/2024] Open
Abstract
With childhood hypertension emerging as a global public health concern, understanding its associated factors is crucial. This study investigated the prevalence and associated factors of hypertension among Chinese children. This cross-sectional investigation was conducted in Pinghu, Zhejiang province, involving 2,373 children aged 8-14 years from 12 schools. Anthropometric measurements were taken by trained staff. Blood pressure (BP) was measured in three separate occasions, with an interval of at least two weeks. Childhood hypertension was defined as systolic blood pressure (SBP) and/or diastolic blood pressure (DBP) ≥ age-, sex-, and height-specific 95th percentile, across all three visits. A self-administered questionnaire was utilized to collect demographic, socioeconomic, health behavioral, and parental information at the first visit of BP measurement. Random forest (RF) and multivariable logistic regression model were used collectively to identify associated factors. Additionally, population attributable fractions (PAFs) were calculated. The prevalence of childhood hypertension was 5.0% (95% confidence interval [CI]: 4.1-5.9%). Children with body mass index (BMI) ≥ 85th percentile were grouped into abnormal weight, and those with waist circumference (WC) > 90th percentile were sorted into central obesity. Normal weight with central obesity (NWCO, adjusted odds ratio [aOR] = 5.04, 95% CI: 1.96-12.98), abnormal weight with no central obesity (AWNCO, aOR = 4.60, 95% CI: 2.57-8.21), and abnormal weight with central obesity (AWCO, aOR = 9.94, 95% CI: 6.06-16.32) were associated with an increased risk of childhood hypertension. Childhood hypertension was attributable to AWCO mostly (PAF: 0.64, 95% CI: 0.50-0.75), followed by AWNCO (PAF: 0.34, 95% CI: 0.19-0.51), and NWCO (PAF: 0.13, 95% CI: 0.03-0.30). Our results indicated that obesity phenotype is associated with childhood hypertension, and the role of weight management could serve as potential target for intervention.
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Affiliation(s)
- Jiali Zhou
- Department of Big Data in Health Science, School of Public Health and The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310051, China
- Department of Nutrition and Food Safety, Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, Zhejiang, 310051, China
| | - Weidi Sun
- Department of Big Data in Health Science, School of Public Health and The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310051, China
| | - Chenhao Zhang
- Department of Big Data in Health Science, School of Public Health and The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310051, China
| | - Leying Hou
- Department of Big Data in Health Science, School of Public Health and The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310051, China
| | - Zeyu Luo
- Department of Big Data in Health Science, School of Public Health and The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310051, China
| | - Denan Jiang
- Department of Big Data in Health Science, School of Public Health and The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310051, China
- The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, Zhejiang, 322000, China
| | - Boren Tan
- Department of Big Data in Health Science, School of Public Health and The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310051, China
| | - Changzheng Yuan
- Department of Big Data in Health Science, School of Public Health and The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310051, China
| | - Dong Zhao
- Department of Nutrition and Food Safety, Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, Zhejiang, 310051, China
| | - Juanjuan Li
- Department of Nutrition and Food Safety, Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, Zhejiang, 310051, China
| | - Ronghua Zhang
- Department of Nutrition and Food Safety, Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, Zhejiang, 310051, China.
| | - Peige Song
- Department of Big Data in Health Science, School of Public Health and The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310051, China.
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Frank N, Herrmann MJ, Lauer M, Förster CY. Exploratory Review of the Takotsubo Syndrome and the Possible Role of the Psychosocial Stress Response and Inflammaging. Biomolecules 2024; 14:167. [PMID: 38397404 PMCID: PMC10886847 DOI: 10.3390/biom14020167] [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: 12/12/2023] [Revised: 01/24/2024] [Accepted: 01/29/2024] [Indexed: 02/25/2024] Open
Abstract
Takotsubo syndrome (TTS) is a cardiomyopathy that clinically presents as a transient and reversible left ventricular wall motion abnormality (LVWMA). Recovery can occur spontaneously within hours or weeks. Studies have shown that it mainly affects older people. In particular, there is a higher prevalence in postmenopausal women. Physical and emotional stress factors are widely discussed and generally recognized triggers. In addition, the hypothalamic-pituitary-adrenal (HPA) axis and the associated glucocorticoid-dependent negative feedback play an important role in the resulting immune response. This review aims to highlight the unstudied aspects of the trigger factors of TTS. The focus is on emotional stress/chronic unpredictable mild stress (CUMS), which is influenced by estrogen concentration and noradrenaline, for example, and can lead to changes in the behavioral, hormonal, and autonomic systems. Age- and gender-specific aspects, as well as psychological effects, must also be considered. We hypothesize that this leads to a stronger corticosteroid response and altered feedback of the HPA axis. This may trigger proinflammatory markers and thus immunosuppression, inflammaging, and sympathetic overactivation, which contributes significantly to the development of TTS. The aim is to highlight the importance of CUMS and psychological triggers as risk factors and to make an exploratory proposal based on the new knowledge. Based on the imbalance between the sympathetic and parasympathetic nervous systems, transcutaneous vagus nerve stimulation (tVNS) is presented as a possible new therapeutic approach.
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Affiliation(s)
- Niklas Frank
- Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, Würzburg University, 97080 Würzburg, Germany
| | - Martin J. Herrmann
- Center of Mental Health, Department of Psychiatry and Psychotherapy, University Hospital Würzburg, 97080 Würzburg, Germany; (M.J.H.); (M.L.)
| | - Martin Lauer
- Center of Mental Health, Department of Psychiatry and Psychotherapy, University Hospital Würzburg, 97080 Würzburg, Germany; (M.J.H.); (M.L.)
| | - Carola Y. Förster
- Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, Würzburg University, 97080 Würzburg, Germany
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Xiao Z, Liu H. The estrogen receptor and metabolism. WOMEN'S HEALTH (LONDON, ENGLAND) 2024; 20:17455057241227362. [PMID: 38420694 PMCID: PMC10903191 DOI: 10.1177/17455057241227362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 12/22/2023] [Accepted: 01/04/2024] [Indexed: 03/02/2024]
Abstract
Across the globe, metabolic syndrome, hyperuric acid, and their related diseases, such as cardiovascular disease, diabetes, and insulin resistance, are increasing in incidence due to metabolic imbalances. Due to the pathogenesis, women are more prone to these diseases than men. As estrogen levels decrease after menopause, obesity and metabolic disorders are more likely to occur. Men are also affected by hyperuric acid. To provide ideas for the prevention and treatment of metabolic syndrome and hyperuricemia, this article reviews and analyzes the relationship between estrogen receptors, metabolic syndrome, and hyperuricemia.
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Affiliation(s)
- Zizi Xiao
- Guangzhou Panyu Central Hospital, Guangzhou, China
| | - Haijun Liu
- Guangzhou Panyu Central Hospital, Guangzhou, China
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Abstract
Heart failure (HF) is a significant public health problem worldwide. It has long been noted that premenopausal women, compared to postmenopausal women and men, have lower rates for developing this disease, as well as subsequent morbidity and mortality. This difference has been attributed to estrogen playing a cardioprotective role in these women, though exactly how it does so remains unclear. In this review, we examine the presence of estrogen receptors within the cardiovascular system, as well as the role they play behind the cardioprotective effect attributed to estrogen. Furthermore, we highlight the underlying mechanisms behind their alleviation of HF, as well as possible treatment approaches, such as hormone replacement therapy and exercise regimens, to manipulate these mechanisms in treating and preventing HF.
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Affiliation(s)
- Chenyue Qian
- The Second Clinical Medical College, Jinan University, Shenzhen, 518020, Guangdong, China
| | - Jingjin Liu
- The Second Clinical Medical College, Jinan University, Shenzhen, 518020, Guangdong, China.
- Department of Cardiology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China.
- Department of Cardiology, Shenzhen Cardiovascular Minimally Invasive Medical Engineering Technology Research and Development Center, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China.
- Shenzhen Key Laboratory of Stem Cell Research and Clinical Transformation, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China.
- Department of GeriatricsThe Second Clinical Medical CollegeThe First Affiliated Hospital, Shenzhen People's HospitalJinan UniversitySouthern University of Science and Technology), Shenzhen, 518020, Guangdong, People's Republic of China.
| | - Huadong Liu
- The Second Clinical Medical College, Jinan University, Shenzhen, 518020, Guangdong, China.
- Department of Cardiology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China.
- Department of Cardiology, Shenzhen Cardiovascular Minimally Invasive Medical Engineering Technology Research and Development Center, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China.
- Shenzhen Key Laboratory of Stem Cell Research and Clinical Transformation, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China.
- Department of GeriatricsThe Second Clinical Medical CollegeThe First Affiliated Hospital, Shenzhen People's HospitalJinan UniversitySouthern University of Science and Technology), Shenzhen, 518020, Guangdong, People's Republic of China.
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Palamarchuk IS, Slavich GM, Vaillancourt T, Rajji TK. Stress-related cellular pathophysiology as a crosstalk risk factor for neurocognitive and psychiatric disorders. BMC Neurosci 2023; 24:65. [PMID: 38087196 PMCID: PMC10714507 DOI: 10.1186/s12868-023-00831-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 10/24/2023] [Indexed: 12/18/2023] Open
Abstract
In this narrative review, we examine biological processes linking psychological stress and cognition, with a focus on how psychological stress can activate multiple neurobiological mechanisms that drive cognitive decline and behavioral change. First, we describe the general neurobiology of the stress response to define neurocognitive stress reactivity. Second, we review aspects of epigenetic regulation, synaptic transmission, sex hormones, photoperiodic plasticity, and psychoneuroimmunological processes that can contribute to cognitive decline and neuropsychiatric conditions. Third, we explain mechanistic processes linking the stress response and neuropathology. Fourth, we discuss molecular nuances such as an interplay between kinases and proteins, as well as differential role of sex hormones, that can increase vulnerability to cognitive and emotional dysregulation following stress. Finally, we explicate several testable hypotheses for stress, neurocognitive, and neuropsychiatric research. Together, this work highlights how stress processes alter neurophysiology on multiple levels to increase individuals' risk for neurocognitive and psychiatric disorders, and points toward novel therapeutic targets for mitigating these effects. The resulting models can thus advance dementia and mental health research, and translational neuroscience, with an eye toward clinical application in cognitive and behavioral neurology, and psychiatry.
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Affiliation(s)
- Iryna S Palamarchuk
- Centre for Addiction and Mental Health, 1001 Queen Street West, Toronto, ON, M6J1H4, Canada.
- Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
- Sunnybrook Health Sciences Centre, Division of Neurology, Toronto, ON, Canada.
- Temerty Faculty of Medicine, Toronto Dementia Research Alliance, University of Toronto, Toronto, ON, Canada.
| | - George M Slavich
- Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA, USA
| | - Tracy Vaillancourt
- Counselling Psychology, Faculty of Education, University of Ottawa, Ottawa, ON, Canada
- School of Psychology, Faculty of Social Sciences, University of Ottawa, Ottawa, ON, Canada
| | - Tarek K Rajji
- Centre for Addiction and Mental Health, 1001 Queen Street West, Toronto, ON, M6J1H4, Canada
- Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Temerty Faculty of Medicine, Toronto Dementia Research Alliance, University of Toronto, Toronto, ON, Canada
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Zhao D, Zhou J, Su D, Li Y, Sun W, Tan B, Li S, Zhang R, Song P. Combined associations of general obesity and central obesity with hypertension stages and phenotypes among children and adolescents in Zhejiang, China. J Clin Hypertens (Greenwich) 2023; 25:983-992. [PMID: 37787088 PMCID: PMC10631097 DOI: 10.1111/jch.14733] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 09/14/2023] [Accepted: 09/15/2023] [Indexed: 10/04/2023]
Abstract
General and central obesity are suggested to be associated with elevated blood pressure (BP), whereas few studies have investigated their combined associations with hypertension in children. This study aimed to assess the associations of combinations of general obesity and central obesity with hypertension in Chinese children, including its stages and phenotypes. A total of 5430 children aged 7-17 years in Zhejiang Province were enrolled. General obesity was evaluated by body mass index (BMI), while central obesity was by waist circumference (WC). Then all children were sorted into three mutually exclusive groups: normal weight with or with no central obesity (NW), abnormal weight with no central obesity (AWNCO), and abnormal weight with central obesity (AWCO). Hypertension was defined as either a systolic or diastolic BP ≥ 95th percentile, and further classified into stage 1 hypertension, stage 2 hypertension, isolated systolic hypertension (ISH), isolated diastolic hypertension (IDH), and systolic diastolic hypertension (SDH). Logistic regression was used. AWNCO and AWCO were associated with stage 1 hypertension (AWNCO, odds ratio [OR] = 1.94, 95% confidence interval [CI]: 1.59-2.37; AWCO, 2.67, 2.20-3.25), stage 2 hypertension (AWNCO, 2.35, 1.33-4.13; AWCO, 4.53, 2.79-7.37), ISH (AWNCO, 2.50, 1.96-3.18; AWCO, 3.95, 3.15-4.95), and SDH (AWNCO, 2.48, 1.75-3.52; AWCO, 2.78, 1.94-3.99). Children with AWCO were more likely to have stage 1 and stage 2 hypertension, as well as ISH and SDH. The combined measurement of general and central obesity is suggested as an appropriate screening tool for hypertension among children and adolescents.
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Affiliation(s)
- Dong Zhao
- Department of Nutrition and Food SafetyZhejiang Provincial Center for Disease Control and PreventionHangzhouZhejiangChina
| | - Jiali Zhou
- Department of Nutrition and Food SafetyZhejiang Provincial Center for Disease Control and PreventionHangzhouZhejiangChina
- School of Public HealthZhejiang University School of MedicineZhejiang UniversityHangzhouZhejiangChina
| | - Danting Su
- Department of Nutrition and Food SafetyZhejiang Provincial Center for Disease Control and PreventionHangzhouZhejiangChina
| | - Yun Li
- Division of Chronic Non‐communicable Disease and Health EducationPinghu Municipal Center for Disease Control and PreventionPinghuZhejiangChina
| | - Weidi Sun
- School of Public HealthZhejiang University School of MedicineZhejiang UniversityHangzhouZhejiangChina
| | - Boren Tan
- School of Public HealthZhejiang University School of MedicineZhejiang UniversityHangzhouZhejiangChina
| | - Shuting Li
- School of Public HealthZhejiang University School of MedicineZhejiang UniversityHangzhouZhejiangChina
| | - Ronghua Zhang
- Department of Nutrition and Food SafetyZhejiang Provincial Center for Disease Control and PreventionHangzhouZhejiangChina
| | - Peige Song
- School of Public HealthZhejiang University School of MedicineZhejiang UniversityHangzhouZhejiangChina
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Nour J, Bonacina F, Norata GD. Gonadal sex vs genetic sex in experimental atherosclerosis. Atherosclerosis 2023; 384:117277. [PMID: 37775425 DOI: 10.1016/j.atherosclerosis.2023.117277] [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: 03/31/2023] [Revised: 06/09/2023] [Accepted: 09/01/2023] [Indexed: 10/01/2023]
Abstract
Epidemiological data and interventional studies with hormone replacement therapy suggest that women, at least until menopause, are at decreased cardiovascular risk compared to men. Still the molecular mechanisms beyond this difference are debated and the investigation in experimental models of atherosclerosis has been pivotal to prove that the activation of the estrogen receptor is atheroprotective, despite not enough to explain the differences reported in cardiovascular disease between male and female. This casts also for investigating the importance of the sex chromosome complement (genetic sex) beyond the contribution of sex hormones (gonadal sex) on atherosclerosis. Aim of this review is to present the dualism between gonadal sex and genetic sex with a focus on the data available from experimental models. The molecular mechanisms driving changes in lipid metabolism, immuno-inflammatory reactivity and vascular response in males and females that affect atherosclerosis progression will be discussed.
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Affiliation(s)
- Jasmine Nour
- Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", University of Milan, Italy
| | - Fabrizia Bonacina
- Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", University of Milan, Italy
| | - Giuseppe D Norata
- Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", University of Milan, Italy.
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Xiang X, Xie L, Lin J, Pare R, Huang G, Huang J, Wang Y, Song S, Ruan Y. Estrogen receptor alpha mediates 17β-estradiol, up-regulates autophagy and alleviates hydrogen peroxide-induced vascular senescence. Biogerontology 2023; 24:783-799. [PMID: 36683095 DOI: 10.1007/s10522-023-10015-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 01/10/2023] [Indexed: 01/24/2023]
Abstract
Atherosclerosis threatens human health by developing cardiovascular diseases, the deadliest disease world widely. The major mechanism contributing to the formation of atherosclerosis is mainly due to vascular endothelial cell (VECs) senescence. We have shown that 17β-estradiol (17β-E2) may protect VECs from senescence by upregulating autophagy. However, little is known about how 17β-E2 activates the autophagy pathway to alleviate cellular senescence. Therefore, the aim of this study is to determine the role of estrogen receptor (ER) α and β in the effects of 17β-E2 on vascular autophagy and aging through in vitro and in vivo models. Hydrogen peroxide (H2O2) was used to establish Human Umbilical Vein Endothelial Cells (HUVECs) senescence. Autophagy activity was measured through immunofluorescence and immunohistochemistry staining of light chain 3 (LC3) expression. Inhibition of ER activity was established using shRNA gene silencing and ER antagonist. Compared with ER-β knockdown, we found that knockdown of ER-α resulted in a significant increase in the extent of HUVEC senescence and senescence-associated secretory phenotype (SASP) secretion. ER-α-specific shRNA was found to reduce 17β-E2-induced autophagy, promote HUVEC senescence, disrupt the morphology of HUVECs, and increase the expression of Rb dephosphorylation and SASP. These in vitro findings were found consistent with the in vivo results. In conclusion, our data suggest that 17β-E2 activates the activity of ER-α and then increases the formation of autophagosomes (LC3 high expression) and decreases the fusion of lysosomes with autophagic vesicles (P62 low expression), which in turn serves to decrease the secretion of SASP caused by H2O2 and consequently inhibit H2O2-induced senescence in HUVEC cells.
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Affiliation(s)
- Xiuting Xiang
- Department of Geriatrics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu, Malaysia
| | - LiangZhen Xie
- Department of Geriatrics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Jieqi Lin
- Department of Geriatrics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Rahmawati Pare
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu, Malaysia
| | - Guanshen Huang
- Department of Geriatrics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Jianming Huang
- Department of Geriatrics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Yuyan Wang
- Department of Geriatrics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Shicong Song
- Department of Geriatrics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Yunjun Ruan
- Department of Geriatrics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.
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Nwia SM, Leite APO, Li XC, Zhuo JL. Sex differences in the renin-angiotensin-aldosterone system and its roles in hypertension, cardiovascular, and kidney diseases. Front Cardiovasc Med 2023; 10:1198090. [PMID: 37404743 PMCID: PMC10315499 DOI: 10.3389/fcvm.2023.1198090] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 06/06/2023] [Indexed: 07/06/2023] Open
Abstract
Cardiovascular disease is a pathology that exhibits well-researched biological sex differences, making it possible for physicians to tailor preventative and therapeutic approaches for various diseases. Hypertension, which is defined as blood pressure greater than 130/80 mmHg, is the primary risk factor for developing coronary artery disease, stroke, and renal failure. Approximately 48% of American men and 43% of American women suffer from hypertension. Epidemiological data suggests that during reproductive years, women have much lower rates of hypertension than men. However, this protective effect disappears after the onset of menopause. Treatment-resistant hypertension affects approximately 10.3 million US adults and is unable to be controlled even after implementing ≥3 antihypertensives with complementary mechanisms. This indicates that other mechanisms responsible for modulating blood pressure are still unclear. Understanding the differences in genetic and hormonal mechanisms that lead to hypertension would allow for sex-specific treatment and an opportunity to improve patient outcomes. Therefore, this invited review will review and discuss recent advances in studying the sex-specific physiological mechanisms that affect the renin-angiotensin system and contribute to blood pressure control. It will also discuss research on sex differences in hypertension management, treatment, and outcomes.
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Affiliation(s)
- Sarah M. Nwia
- Tulane Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, LA, United States
- Department of Physiology, Tulane University School of Medicine, New Orleans, LA, United States
| | - Ana Paula O. Leite
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, United States
| | - Xiao Chun Li
- Tulane Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, LA, United States
- Department of Physiology, Tulane University School of Medicine, New Orleans, LA, United States
| | - Jia Long Zhuo
- Tulane Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, LA, United States
- Department of Physiology, Tulane University School of Medicine, New Orleans, LA, United States
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11
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Guthrie GL, Almutlaq RN, Sugahara S, Butt MK, Brooks CR, Pollock DM, Gohar EY. G protein-coupled estrogen receptor 1 regulates renal endothelin-1 signaling system in a sex-specific manner. Front Physiol 2023; 14:1086973. [PMID: 36733911 PMCID: PMC9887121 DOI: 10.3389/fphys.2023.1086973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 01/06/2023] [Indexed: 01/19/2023] Open
Abstract
Demographic studies reveal lower prevalence of hypertension among premenopausal females compared to age-matched males. The kidney plays a central role in the maintenance of sodium (Na+) homeostasis and consequently blood pressure. Renal endothelin-1 (ET-1) is a pro-natriuretic peptide that contributes to sex differences in blood pressure regulation and Na+ homeostasis. We recently showed that activation of renal medullary G protein-coupled estrogen receptor 1 (GPER1) promotes ET-1-dependent natriuresis in female, but not male, rats. We hypothesized that GPER1 upregulates the renal ET-1 signaling system in females, but not males. To test our hypothesis, we determined the effect of GPER1 deletion on ET-1 and its downstream effectors in the renal cortex, outer and inner medulla obtained from 12-16-week-old female and male mice. GPER1 knockout (KO) mice and wildtype (WT) littermates were implanted with telemetry transmitters for blood pressure assessment, and we used metabolic cages to determine urinary Na+ excretion. GPER1 deletion did not significantly affect 24-h mean arterial pressure (MAP) nor urinary Na+ excretion. However, GPER1 deletion decreased urinary ET-1 excretion in females but not males. Of note, female WT mice had greater urinary ET-1 excretion than male WT littermates, whereas no sex differences were observed in GPER1 KO mice. GPER1 deletion increased inner medullary ET-1 peptide content in both sexes but increased outer medullary ET-1 content in females only. Cortical ET-1 content increased in response to GPER1 deletion in both sexes. Furthermore, GPER1 deletion notably increased inner medullary ET receptor A (ETA) and decreased outer medullary ET receptor B (ETB) mRNA expression in male, but not female, mice. We conclude that GPER1 is required for greater ET-1 excretion in females. Our data suggest that GPER1 is an upstream regulator of renal medullary ET-1 production and ET receptor expression in a sex-specific manner. Overall, our study identifies the role of GPER1 as a sex-specific upstream regulator of the renal ET-1 system.
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Affiliation(s)
- Ginger L. Guthrie
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Rawan N. Almutlaq
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Sho Sugahara
- Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Maryam K. Butt
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Craig R. Brooks
- Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, TN, United States
| | - David M. Pollock
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Eman Y. Gohar
- Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, TN, United States,*Correspondence: Eman Y. Gohar,
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12
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Tissue Derivation and Biological Sex Uniquely Mediate Endothelial Cell Protein Expression, Redox Status, and Nitric Oxide Synthesis. Cells 2022; 12:cells12010093. [PMID: 36611888 PMCID: PMC9818567 DOI: 10.3390/cells12010093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 12/17/2022] [Accepted: 12/19/2022] [Indexed: 12/28/2022] Open
Abstract
Human endothelial cells are routinely utilized in cardiovascular research to provide a translational foundation for understanding how the vascular endothelium functions in vivo. However, little attention has been given to whether there are sex specific responses in vitro. Similarly, it is unclear whether endothelial cells derived from distinct tissues behave in a homogenous manner. Herein, we demonstrate that marked sex differences exist within, and between, commonly utilized human primary endothelial cells from healthy donors, with respect to redox status, nitric oxide synthesis, and associated proteins that can mediate their expression. Further, we demonstrate that endothelial cells respond uniquely to inflammatory insult in a sex- and tissue origin-dependent manner. Our findings suggest sex and tissue derivation may need to be considered when studying endothelial cells in vitro as cells derived from distinct tissue and sexes may not behave interchangeably.
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13
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Ahluwalia A, Hoa N, Moreira D, Aziz D, Singh K, Patel KN, Levin ER. Membrane Estrogen Receptor β Is Sufficient to Mitigate Cardiac Cell Pathology. Endocrinology 2022; 164:6867852. [PMID: 36461668 DOI: 10.1210/endocr/bqac200] [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: 08/15/2022] [Revised: 11/23/2022] [Accepted: 11/28/2022] [Indexed: 12/04/2022]
Abstract
Estrogen acting through estrogen receptor β (ERβ) has been shown to oppose the stimulation of cardiac myocytes and cardiac fibroblasts that results in cardiac hypertrophy and fibrosis. Previous work has implicated signal transduction from ERβ as being important to the function of estrogen in this regard. Here we address whether membrane ERβ is sufficient to oppose key mechanisms by which angiotensin II (AngII) stimulates cardiac cell pathology. To do this we first defined essential structural elements within ERβ that are necessary for membrane or nuclear localization in cells. We previously determined that cysteine 418 is the site of palmitoylation of ERβ that is required and sufficient for cell membrane localization in mice and is the same site in humans. Here we determined in Chinese hamster ovarian (CHO) cells, and mouse and rat myocytes and cardiac fibroblasts, the effect on multiple aspects of signal transduction by expressing wild-type (WT ) or a C418A-mutant ERβ. To test the importance of the nuclear receptor, we determined a 4-amino acid deletion in the E domain of ERβ that strongly blocked nuclear localization. Using these tools, we expressed WT and mutant ERβ constructs into cardiomyocytes and cardiac fibroblasts from ERβ-deleted mice. We determined the ability of estrogen to mitigate cell pathology stimulated by AngII and whether the membrane ERβ is necessary and sufficient.
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Affiliation(s)
- Amrita Ahluwalia
- Division of Endocrinology, Department of Veterans Affairs, Medical Center, Long Beach, Long Beach, California 90822, USA
| | - Neil Hoa
- Division of Endocrinology, Department of Veterans Affairs, Medical Center, Long Beach, Long Beach, California 90822, USA
| | - Debbie Moreira
- Division of Endocrinology, Department of Veterans Affairs, Medical Center, Long Beach, Long Beach, California 90822, USA
| | - Daniel Aziz
- Division of Endocrinology, Department of Veterans Affairs, Medical Center, Long Beach, Long Beach, California 90822, USA
| | - Karanvir Singh
- Division of Endocrinology, Department of Veterans Affairs, Medical Center, Long Beach, Long Beach, California 90822, USA
| | - Khushin N Patel
- Division of Endocrinology, Department of Veterans Affairs, Medical Center, Long Beach, Long Beach, California 90822, USA
| | - Ellis R Levin
- Division of Endocrinology, Department of Veterans Affairs, Medical Center, Long Beach, Long Beach, California 90822, USA
- Department of Medicine, University of California, Irvine, Irvine, California 92717, USA
- Department of Biochemistry, University of California, Irvine, Irvine, California 92717, USA
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14
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Muhammad A, Forcados GE, Yusuf AP, Abubakar MB, Sadiq IZ, Elhussin I, Siddique MAT, Aminu S, Suleiman RB, Abubakar YS, Katsayal BS, Yates CC, Mahavadi S. Comparative G-Protein-Coupled Estrogen Receptor (GPER) Systems in Diabetic and Cancer Conditions: A Review. Molecules 2022; 27:molecules27248943. [PMID: 36558071 PMCID: PMC9786783 DOI: 10.3390/molecules27248943] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 12/05/2022] [Accepted: 12/08/2022] [Indexed: 12/23/2022] Open
Abstract
For many patients, diabetes Mellitus and Malignancy are frequently encountered comorbidities. Diabetes affects approximately 10.5% of the global population, while malignancy accounts for 29.4 million cases each year. These troubling statistics indicate that current treatment approaches for these diseases are insufficient. Alternative therapeutic strategies that consider unique signaling pathways in diabetic and malignancy patients could provide improved therapeutic outcomes. The G-protein-coupled estrogen receptor (GPER) is receiving attention for its role in disease pathogenesis and treatment outcomes. This review aims to critically examine GPER' s comparative role in diabetes mellitus and malignancy, identify research gaps that need to be filled, and highlight GPER's potential as a therapeutic target for diabetes and malignancy management. There is a scarcity of data on GPER expression patterns in diabetic models; however, for diabetes mellitus, altered expression of transport and signaling proteins has been linked to GPER signaling. In contrast, GPER expression in various malignancy types appears to be complex and debatable at the moment. Current data show inconclusive patterns of GPER expression in various malignancies, with some indicating upregulation and others demonstrating downregulation. Further research should be conducted to investigate GPER expression patterns and their relationship with signaling pathways in diabetes mellitus and various malignancies. We conclude that GPER has therapeutic potential for chronic diseases such as diabetes mellitus and malignancy.
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Affiliation(s)
- Aliyu Muhammad
- Center for Cancer Research, Department of Biology, Tuskegee University, Tuskegee, AL 36088, USA
- Department of Biochemistry, Faculty of Life Sciences, Ahmadu Bello University, Zaria P.M.B. 1044, Nigeria
| | | | - Abdurrahman Pharmacy Yusuf
- Department of Biochemistry, School of Life Sciences, Federal University of Technology, Minna P.M.B. 65, Nigeria
| | - Murtala Bello Abubakar
- Department of Physiology, Faculty of Basic Medical Sciences, College of Health Sciences, Usmanu Danfodiyo University, Sokoto P.M.B. 2254, Nigeria
- Centre for Advanced Medical Research & Training (CAMRET), Usmanu Danfodiyo University, Sokoto P.M.B. 2254, Nigeria
| | - Idris Zubairu Sadiq
- Department of Biochemistry, Faculty of Life Sciences, Ahmadu Bello University, Zaria P.M.B. 1044, Nigeria
| | - Isra Elhussin
- Center for Cancer Research, Department of Biology, Tuskegee University, Tuskegee, AL 36088, USA
| | - Md Abu Talha Siddique
- Center for Cancer Research, Department of Biology, Tuskegee University, Tuskegee, AL 36088, USA
| | - Suleiman Aminu
- Department of Biochemistry, Faculty of Life Sciences, Ahmadu Bello University, Zaria P.M.B. 1044, Nigeria
| | - Rabiatu Bako Suleiman
- Department of Biochemistry, Faculty of Life Sciences, Ahmadu Bello University, Zaria P.M.B. 1044, Nigeria
| | - Yakubu Saddeeq Abubakar
- Department of Biochemistry, Faculty of Life Sciences, Ahmadu Bello University, Zaria P.M.B. 1044, Nigeria
| | - Babangida Sanusi Katsayal
- Department of Biochemistry, Faculty of Life Sciences, Ahmadu Bello University, Zaria P.M.B. 1044, Nigeria
| | - Clayton C Yates
- Center for Cancer Research, Department of Biology, Tuskegee University, Tuskegee, AL 36088, USA
| | - Sunila Mahavadi
- Center for Cancer Research, Department of Biology, Tuskegee University, Tuskegee, AL 36088, USA
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15
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Woods C, Contoreggi NH, Johnson MA, Milner TA, Wang G, Glass MJ. Estrogen receptor beta activity contributes to both tumor necrosis factor alpha expression in the hypothalamic paraventricular nucleus and the resistance to hypertension following angiotensin II in female mice. Neurochem Int 2022; 161:105420. [PMID: 36170907 PMCID: PMC11575694 DOI: 10.1016/j.neuint.2022.105420] [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: 07/27/2022] [Revised: 09/13/2022] [Accepted: 09/20/2022] [Indexed: 12/26/2022]
Abstract
Sex differences in the sensitivity to hypertension and inflammatory processes are well characterized but insufficiently understood. In male mice, tumor necrosis factor alpha (TNFα) in the hypothalamic paraventricular nucleus (PVN) contributes to hypertension following slow-pressor angiotensin II (AngII) infusion. However, the role of PVN TNFα in the response to AngII in female mice is unknown. Using a combination of in situ hybridization, high-resolution electron microscopic immunohistochemistry, spatial-temporal gene silencing, and dihydroethidium microfluorography we investigated the influence of AngII on both blood pressure and PVN TNFα signaling in female mice. We found that chronic (14-day) infusion of AngII in female mice did not impact blood pressure, TNFα levels, the expression of the TNFα type 1 receptor (TNFR1), or the subcellular distribution of TNFR1 in the PVN. However, it was shown that blockade of estrogen receptor β (ERβ), a major hypothalamic estrogen receptor, was accompanied by both elevated PVN TNFα and hypertension following AngII. Further, AngII hypertension following ERβ blockade was attenuated by inhibiting PVN TNFα signaling by local TNFR1 silencing. It was also shown that ERβ blockade in isolated PVN-spinal cord projection neurons (i.e. sympathoexcitatory) heightened TNFα-induced production of NADPH oxidase (NOX2)-mediated reactive oxygen species, molecules that may play a key role in mediating the effect of TNFα in hypertension. These results indicate that ERβ contributes to the reduced sensitivity of female mice to hypothalamic inflammatory cytokine signaling and hypertension in response to AngII.
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Affiliation(s)
- Clara Woods
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Natalina H Contoreggi
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Megan A Johnson
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Teresa A Milner
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, 10065, USA; Harold and Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, 10065, USA
| | - Gang Wang
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Michael J Glass
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, 10065, USA.
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16
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Maruyama NO, Estrela HF, Sales EBO, Lucas TF, Porto CS, Bergamaschi CT, Campos RR. Differential effects of estrogen receptors in the rostral ventrolateral medulla in Goldblatt hypertension. J Steroid Biochem Mol Biol 2022; 224:106176. [PMID: 36087695 DOI: 10.1016/j.jsbmb.2022.106176] [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: 06/09/2022] [Revised: 08/31/2022] [Accepted: 09/01/2022] [Indexed: 11/18/2022]
Abstract
Previous studies have shown that 17β-estradiol plays a cardioprotective role in the central nervous system (CNS) of male rats. The aim of the present study was to determine the influence of 17β-estradiol on sympathetic vasomotor activity and blood pressure in a renovascular hypertensive Goldblatt two-kidney one-clip (2K-1C) male rat model. We also determined the influence of angiotensin II AT1 receptor on the expression of estrogen receptors (ERα, ERβ, and G protein-coupled ER (GPER)) in the rostral ventrolateral medulla (RVLM) of Goldblatt rats. Experiments were performed in Goldblatt and age-matched control rats six weeks after clipping of renal artery to induce hypertension. Microinjection of 17β-estradiol into the RVLM led to a greater reduction in mean arterial pressure and renal sympathetic nerve activity in controls than in 2K-1C rats. Microinjection of the GPER agonist G-1 into the RVLM led to a significantly greater increase in mean arterial pressure and renal sympathetic nerve activity in 2K-1C rats. Expression levels of estrogen receptors GPER and ERα, but not ERβ, were significantly higher in the RVLM of 2K-1C rats than in that of the control rats. Chronic treatment with losartan significantly reduced the expression levels of estrogen receptors in the RVLM of 2K-1C rats. Taken altogether, the data suggest that the imbalance of actions between ERα and GPER, particularly with the predominance of GPER in the RVLM, contributes to sympathetic overactivation in male rats with Goldblatt hypertension. AT1-Angiotensin II receptor in the RVLM upregulated estrogen receptor expression in male Goldblatt rats.
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Affiliation(s)
- N O Maruyama
- Department of Physiology, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
| | - H F Estrela
- Department of Physiology, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
| | - E B Oliveira Sales
- Department of Physiology, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
| | - T F Lucas
- Laboratory of Experimental Endocrinology, Department of Pharmacology, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
| | - C S Porto
- Laboratory of Experimental Endocrinology, Department of Pharmacology, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
| | - C T Bergamaschi
- Department of Physiology, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
| | - R R Campos
- Department of Physiology, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil.
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17
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Monsour M, Gordon J, Lockard G, Alayli A, Elsayed B, Connolly J, Borlongan CV. Minor Changes for a Major Impact: A Review of Epigenetic Modifications in Cell-Based Therapies for Stroke. Int J Mol Sci 2022; 23:13106. [PMID: 36361891 PMCID: PMC9656972 DOI: 10.3390/ijms232113106] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 10/25/2022] [Accepted: 10/26/2022] [Indexed: 08/16/2024] Open
Abstract
Epigenetic changes in stroke may revolutionize cell-based therapies aimed at reducing ischemic stroke risk and damage. Epigenetic changes are a novel therapeutic target due to their specificity and potential for reversal. Possible targets for epigenetic modification include DNA methylation and demethylation, post-translational histone modification, and the actions of non-coding RNAs such as microRNAs. Many of these epigenetic modifications have been reported to modulate atherosclerosis development and progression, ultimately contributing to stroke pathogenesis. Furthermore, epigenetics may play a major role in inflammatory responses following stroke. Stem cells for stroke have demonstrated safety in clinical trials for stroke and show therapeutic benefit in pre-clinical studies. The efficacy of these cell-based interventions may be amplified with adjunctive epigenetic modifications. This review advances the role of epigenetics in atherosclerosis and inflammation in the context of stroke, followed by a discussion on current stem cell studies modulating epigenetics to ameliorate stroke damage.
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Affiliation(s)
- Molly Monsour
- University of South Florida Morsani College of Medicine, Tampa, FL 33602, USA
| | - Jonah Gordon
- University of South Florida Morsani College of Medicine, Tampa, FL 33602, USA
| | - Gavin Lockard
- University of South Florida Morsani College of Medicine, Tampa, FL 33602, USA
| | - Adam Alayli
- University of South Florida Morsani College of Medicine, Tampa, FL 33602, USA
| | - Bassel Elsayed
- University of South Florida Morsani College of Medicine, Tampa, FL 33602, USA
| | - Jacob Connolly
- University of South Florida Morsani College of Medicine, Tampa, FL 33602, USA
| | - Cesar V. Borlongan
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA
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18
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Cianci R, Franza L, Borriello R, Pagliari D, Gasbarrini A, Gambassi G. The Role of Gut Microbiota in Heart Failure: When Friends Become Enemies. Biomedicines 2022; 10:2712. [PMID: 36359233 PMCID: PMC9687270 DOI: 10.3390/biomedicines10112712] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 10/20/2022] [Accepted: 10/22/2022] [Indexed: 10/29/2023] Open
Abstract
Heart failure is a complex health issue, with important consequences on the overall wellbeing of patients. It can occur both in acute and chronic forms and, in the latter, the immune system appears to play an important role in the pathogenesis of the disease. In particular, in the forms with preserved ejection fraction or with only mildly reduced ejection fraction, some specific associations with chronic inflammatory diseases have been observed. Another interesting aspect that is worth considering is the role of microbiota modulation, in this context: given the importance of microbiota in the modulation of immune responses, it is possible that changes in its composition may somewhat influence the progression and even the pathogenesis of heart failure. In this narrative review, we aim to examine the relationship between immunity and heart failure, with a special focus on the role of microbiota in this pathological condition.
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Affiliation(s)
- Rossella Cianci
- Department of Translational Medicine and Surgery, Catholic University of Rome, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy
| | - Laura Franza
- Emergency Medicine Unit, Catholic University of Rome, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy
| | - Raffaele Borriello
- Department of Translational Medicine and Surgery, Catholic University of Rome, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy
| | - Danilo Pagliari
- Medical Officer of the Carabinieri Corps, Health Service of the Carabinieri General Headquarters, 00197 Rome, Italy
| | - Antonio Gasbarrini
- Department of Translational Medicine and Surgery, Catholic University of Rome, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy
| | - Giovanni Gambassi
- Department of Translational Medicine and Surgery, Catholic University of Rome, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy
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19
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Guajardo-Correa E, Silva-Agüero JF, Calle X, Chiong M, Henríquez M, García-Rivas G, Latorre M, Parra V. Estrogen signaling as a bridge between the nucleus and mitochondria in cardiovascular diseases. Front Cell Dev Biol 2022; 10:968373. [PMID: 36187489 PMCID: PMC9516331 DOI: 10.3389/fcell.2022.968373] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 08/25/2022] [Indexed: 11/29/2022] Open
Abstract
Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide. Epidemiological studies indicate that pre-menopausal women are more protected against the development of CVDs compared to men of the same age. This effect is attributed to the action/effects of sex steroid hormones on the cardiovascular system. In this context, estrogen modulates cardiovascular function in physiological and pathological conditions, being one of the main physiological cardioprotective agents. Here we describe the common pathways and mechanisms by which estrogens modulate the retrograde and anterograde communication between the nucleus and mitochondria, highlighting the role of genomic and non-genomic pathways mediated by estrogen receptors. Additionally, we discuss the presumable role of bromodomain-containing protein 4 (BRD4) in enhancing mitochondrial biogenesis and function in different CVD models and how this protein could act as a master regulator of estrogen protective activity. Altogether, this review focuses on estrogenic control in gene expression and molecular pathways, how this activity governs nucleus-mitochondria communication, and its projection for a future generation of strategies in CVDs treatment.
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Affiliation(s)
- Emanuel Guajardo-Correa
- Advanced Center of Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas y Facultad de Medicina, Universidad de Chile, Santiago, Chile
- Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile
| | - Juan Francisco Silva-Agüero
- Advanced Center of Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas y Facultad de Medicina, Universidad de Chile, Santiago, Chile
- Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile
| | - Ximena Calle
- Advanced Center of Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas y Facultad de Medicina, Universidad de Chile, Santiago, Chile
- Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile
- Escuela de Química y Farmacia, Facultad de Medicina, Universidad Andres Bello, Santiago, Chile
- Center of Applied Nanoscience (CANS), Facultad de Ciencias Exactas, Universidad Andres Bello, Santiago, Chile
| | - Mario Chiong
- Advanced Center of Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas y Facultad de Medicina, Universidad de Chile, Santiago, Chile
- Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile
| | - Mauricio Henríquez
- Programa de Fisiología y Biofísica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
- Red para el Estudio de Enfermedades Cardiopulmonares de Alta Letalidad (REECPAL), Universidad de Chile, Santiago, Chile
| | - Gerardo García-Rivas
- Tecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Nuevo León, Mexico
- Tecnológico de Monterrey, The Institute for Obesity Research, Hospital Zambrano Hellion, San Pedro Garza Garcia, Nuevo León, Mexico
| | - Mauricio Latorre
- Laboratorio de Bioingeniería, Instituto de Ciencias de la Ingeniería, Universidad de O’Higgins, Rancagua, Chile
- Laboratorio de Bioinformática y Expresión Génica, INTA, Universidad de Chile, Santiago, Chile
| | - Valentina Parra
- Advanced Center of Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas y Facultad de Medicina, Universidad de Chile, Santiago, Chile
- Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile
- Red para el Estudio de Enfermedades Cardiopulmonares de Alta Letalidad (REECPAL), Universidad de Chile, Santiago, Chile
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20
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Miyamoto K, Hasuike S, Kugo H, Sukketsiri W, Moriyama T, Zaima N. Administration of Isoflavone Attenuates Ovariectomy-induced Degeneration of Aortic Wall. J Oleo Sci 2022; 71:889-896. [PMID: 35584959 DOI: 10.5650/jos.ess22043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Women are more resistant to vascular diseases; however, the resistance is reduced after menopause. It has been reported that the risk of vascular diseases such as atherosclerosis and abdominal aortic aneurysm is increased in postmenopausal women. Currently, methods to prevent vascular disease in postmenopausal women have not been established. Isoflavones are promising functional food factors that have a chemical structure similar to estrogen. In this study, we investigated the effects of isoflavones on ovariectomized (OVX)-induced degeneration of the aortic wall in mice. Increased destruction of elastic fibers in the thoracic and abdominal aorta was observed in the OVX group, and isoflavones attenuated the destruction of elastic fibers. The positive areas of matrix metalloproteinase (MMP)-2 and MMP-9 in the OVX group were higher than those in the control group. Isoflavones decreased the positive areas of MMP-2 and MMP-9 compared to those in the OVX group. These data suggest that isoflavones have a suppressive effect on OVX-induced degeneration of the aortic wall by inhibiting the increase in MMP-2 and MMP-9.
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Affiliation(s)
| | | | - Hirona Kugo
- Graduate School of Agriculture, Kindai University
| | - Wanida Sukketsiri
- Pharmacology Program, Division of Health and Applied Sciences, Faculty of Science, Prince of Songkla University
| | - Tatsuya Moriyama
- Graduate School of Agriculture, Kindai University.,Agricultural Technology and Innovation Research Institute, Kindai University
| | - Nobuhiro Zaima
- Graduate School of Agriculture, Kindai University.,Agricultural Technology and Innovation Research Institute, Kindai University
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21
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Waqar A, Jain A, Joseph C, Srivastava K, Ochuba O, Alkayyali T, Poudel S. Cardioprotective Role of Estrogen in Takotsubo Cardiomyopathy. Cureus 2022; 14:e22845. [PMID: 35382214 PMCID: PMC8977075 DOI: 10.7759/cureus.22845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Accepted: 03/04/2022] [Indexed: 11/21/2022] Open
Abstract
Takotsubo cardiomyopathy (TC) is a rare, reversible cause of left ventricular wall motion abnormality (LVWMA) that mimics the presentation of acute myocardial infarction (AMI). TC is usually preceded by an emotional or physical stressor and appears to be more common in postmenopausal women. Various pathophysiological hypotheses of TC have been proposed, but the exact mechanism of action remains elusive. Elevated levels of catecholamines leading to cardiac dysfunction are the most prevalent hypothesis. The protective role of estrogen in the development of cardiomyopathies has been studied extensively. International Takotsubo Diagnostic Criteria (InterTAK) and Mayo clinic diagnostic criteria both have the stipulation stating prevalence of TC is higher in postmenopausal women which hints towards the protective role of estrogen in the development of TC. To review the protective role of estrogen in the mechanism of this novel pathology, we searched Pubmed and Google scholar for the relevant articles by using keywords such as: “takotsubo cardiomyopathy”, “apical ballooning”, “broken heart syndrome”, “stress cardiomyopathy”, “left ventricle wall motion abnormality”, “estrogen”, “estradiol” and “sex hormones”. Our research revealed that although the prevalence of TC is greater in postmenopausal women as compared to men, the prognosis is worse in men. It also revealed the involvement of multiple cellular pathways under the influence of estrogen that could explain the cardioprotective effect of estrogen. Most of the articles found were based on animal studies, thus, there is an emphasis on future human studies. However, we strongly suggest evaluating estrogen levels as part of the initial workup for any patient presenting with signs and symptoms of cardiac pathology.
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22
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Losada-García A, Cortés-Ramírez SA, Cruz-Burgos M, Morales-Pacheco M, Cruz-Hernández CD, Gonzalez-Covarrubias V, Perez-Plascencia C, Cerbón MA, Rodríguez-Dorantes M. Hormone-Related Cancer and Autoimmune Diseases: A Complex Interplay to be Discovered. Front Genet 2022; 12:673180. [PMID: 35111194 PMCID: PMC8801914 DOI: 10.3389/fgene.2021.673180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Accepted: 12/06/2021] [Indexed: 11/17/2022] Open
Abstract
Neoplasic transformation is a continuous process that occurs in the body. Even before clinical signs, the immune system is capable of recognizing these aberrant cells and reacting to suppress them. However, transformed cells acquire the ability to evade innate and adaptive immune defenses through the secretion of molecules that inhibit immune effector functions, resulting in tumor progression. Hormones have the ability to modulate the immune system and are involved in the pathogenesis of autoimmune diseases, and cancer. Hormones can control both the innate and adaptive immune systems in men and women. For example androgens reduce immunity through modulating the production of pro-inflammatory and anti-inflammatory mediators. Women are more prone than men to suffer from autoimmune diseases such as systemic lupus erythematosus, psoriasis and others. This is linked to female hormones modulating the immune system. Patients with autoimmune diseases consistently have an increased risk of cancer, either as a result of underlying immune system dysregulation or as a side effect of pharmaceutical treatments. Epidemiological data on cancer incidence emphasize the link between the immune system and cancer. We outline and illustrate the occurrence of hormone-related cancer and its relationship to the immune system or autoimmune diseases in this review. It is obvious that some observations are contentious and require explanation of molecular mechanisms and validation. As a result, future research should clarify the molecular pathways involved, including any causal relationships, in order to eventually allocate information that will aid in the treatment of hormone-sensitive cancer and autoimmune illness.
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Affiliation(s)
- A Losada-García
- Laboratorio de Oncogenomica Instituto Nacional de Medicina Genomica, Mexico City, Mexico
| | - SA Cortés-Ramírez
- Laboratorio de Oncogenomica Instituto Nacional de Medicina Genomica, Mexico City, Mexico
| | - M Cruz-Burgos
- Laboratorio de Oncogenomica Instituto Nacional de Medicina Genomica, Mexico City, Mexico
| | - M Morales-Pacheco
- Laboratorio de Oncogenomica Instituto Nacional de Medicina Genomica, Mexico City, Mexico
- Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología-Facultad de Química, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | | | | | - Carlos Perez-Plascencia
- Unidad de Genómica y Cáncer, Subdirección de Investigación Básica, INCan, SSA and Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - MA Cerbón
- Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología-Facultad de Química, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - M Rodríguez-Dorantes
- Laboratorio de Oncogenomica Instituto Nacional de Medicina Genomica, Mexico City, Mexico
- *Correspondence: M Rodríguez-Dorantes,
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Nagai M, Förster CY, Dote K. Sex Hormone-Specific Neuroanatomy of Takotsubo Syndrome: Is the Insular Cortex a Moderator? Biomolecules 2022; 12:biom12010110. [PMID: 35053258 PMCID: PMC8773903 DOI: 10.3390/biom12010110] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Accepted: 01/06/2022] [Indexed: 02/04/2023] Open
Abstract
Takotsubo syndrome (TTS), a transient form of dysfunction in the heart’s left ventricle, occurs predominantly in postmenopausal women who have emotional stress. Earlier studies support the concept that the human circulatory system is modulated by a cortical network (consisting of the anterior cingulate gyrus, amygdala, and insular cortex (Ic)) that plays a pivotal role in the central autonomic nervous system in relation to emotional stressors. The Ic plays a crucial role in the sympathovagal balance, and decreased levels of female sex hormones have been speculated to change functional cerebral asymmetry, with a possible link to autonomic instability. In this review, we focus on the Ic as an important moderator of the human brain–heart axis in association with sex hormones. We also summarize the current knowledge regarding the sex-specific neuroanatomy in TTS.
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Affiliation(s)
- Michiaki Nagai
- Department of Cardiology, Hiroshima City Asa Hospital, Hiroshima 731-0293, Japan;
- Correspondence: ; Tel.: +81-82-815-5211; Fax: +81-82-814-1791
| | - Carola Yvette Förster
- Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, University of Würzburg, D-97080 Würzburg, Germany;
| | - Keigo Dote
- Department of Cardiology, Hiroshima City Asa Hospital, Hiroshima 731-0293, Japan;
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24
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Sex steroids receptors, hypertension, and vascular ageing. J Hum Hypertens 2022; 36:120-125. [PMID: 34230581 PMCID: PMC8850193 DOI: 10.1038/s41371-021-00576-7] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 06/18/2021] [Accepted: 06/28/2021] [Indexed: 02/06/2023]
Abstract
Sex hormone receptors are expressed throughout the vasculature and play an important role in the modulation of blood pressure in health and disease. The functions of these receptors may be important in the understanding of sexual dimorphism observed in the pathophysiology of both hypertension and vascular ageing. The interconnectivity of these factors can be exemplified in postmenopausal females, who with age and estrogen deprivation, surpass males with regard to hypertension prevalence, despite experiencing significantly less disease burden in their estrogen replete youth. Estrogen and androgen receptors mediate their actions via direct genomic effects or rapid non-genomic signaling, involving a host of mediators. The expression and subtype composition of these receptors changes through the lifespan in response to age, disease and hormonal exposure. These factors may promote sex steroid receptor-mediated alterations to the Renin-Angiotensin-Aldosterone System (RAAS), and increases in oxidative stress and inflammation, thereby contributing to the development of hypertension and vascular injury with age.
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Abstract
Sirtuin1 is a nutrient-sensitive class III histone deacetylase which is a well-known regulator of organismal lifespan. It has been extensively studied for its role in metabolic regulation as well. Along with its involvement in ageing and metabolism, Sirtuin1 directly deacetylates many critical proteins controlling cardiovascular pathophysiology. Studies using conditional expression and deletion of Sirtuin1 have revealed that it functions in a highly tissue/organ-specific manner. In the vasculature, Sirtuin1 controls endothelial homoeostasis by governing the expression of inflammatory mediators, oxidants and essential transcription factors. Adding to this complexity, Sirtuin1 expression and/or function is also governed by some of these target proteins. Therefore, the importance of better understanding the organ and tissue specificity of Sirtuin1 is highly desirable. Considering the huge volume of research done in this field, this review focuses on Sirtuin1 targets regulating vascular endothelial function. Here, we summarize the discovery of Sirtuin1 as a transcription controller and the further identification of direct target proteins involved in the vascular physiology. Overall, this review presents a holistic picture of the complex cross-talk involved in the molecular regulation of vascular physiology by Sirtuin1.
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Affiliation(s)
- Jitendra Kumar
- François M. Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA
| | - Santosh Kumar
- François M. Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA
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Hajializadeh Z, Khaksari M. The protective effects of 17-β estradiol and SIRT1 against cardiac hypertrophy: a review. Heart Fail Rev 2021; 27:725-738. [PMID: 34537933 DOI: 10.1007/s10741-021-10171-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/07/2021] [Indexed: 12/27/2022]
Abstract
One of the major causes of morbidity and mortality worldwide is cardiac hypertrophy (CH), which leads to heart failure. Sex differences in CH can be caused by sex hormones or their receptors. The incidence of CH increases in postmenopausal women due to the decrease in female sex hormone 17-β estradiol (E2) during menopause. E2 and its receptors inhibit CH in humans and animal models. Silent information regulator 1 (SIRT1) is a NAD+-dependent HDAC (histone deacetylase) and plays a major role in biological processes, such as inflammation, apoptosis, and oxidative stress responses. Probably SIRT1 because of these effects, is one of the main suppressors of CH and has a cardioprotective effect. On the other hand, estrogen and its agonists are highly efficient in modulating SIRT1 expression. In the present study, we review the protective effects of E2 and SIRT1 against CH.
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Affiliation(s)
- Zahra Hajializadeh
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Mohammad Khaksari
- Endocrinology and Metabolism Research Center, Kerman University of Medical Sciences, Kerman, Iran.
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27
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The vascular endothelial growth factor trap aflibercept induces vascular dysfunction and hypertension via attenuation of eNOS/NO signaling in mice. Acta Pharmacol Sin 2021; 42:1437-1448. [PMID: 33303990 PMCID: PMC8379246 DOI: 10.1038/s41401-020-00569-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 10/29/2020] [Indexed: 12/22/2022] Open
Abstract
Aflibercept, as a soluble decoy vascular endothelial growth factor receptor, Which has been used as a first-line monotherapy for cancers. Aflibercept often causes cardiovascular toxicities including hypertension, but the mechanisms underlying aflibercept-induced hypertension remain unknown. In this study we investigated the effect of short-term and long-term administration of aflibercept on blood pressure (BP), vascular function, NO bioavailability, oxidative stress and endothelin 1 (ET-1) in mice and cultured endothelial cells. We showed that injection of a single-dose of aflibercept (18.2, 36.4 mg/kg, iv) rapidly and dose-dependently elevated BP in mice. Aflibercept treatment markedly impaired endothelial-dependent relaxation (EDR) and resulted in NADPH oxidases 1 (NOX1)- and NADPH oxidases 4 (NOX4)-mediated generation of ROS, decreased the activation of protein kinase B (Akt) and endothelial nitric oxide synthase (eNOS) concurrently with a reduction in nitric oxide (NO) production and elevation of ET-1 levels in mouse aortas; these effects were greatly attenuated by supplementation of L-arginine (L-arg, 0.5 or 1.0 g/kg, bid, ig) before aflibercept injection. Similar results were observed in L-arg-pretreated cultured endothelial cells, showing markedly decreased ROS accumulation and AKT/eNOS/NO signaling impairment induced by aflibercept. In order to assess the effects of long-term aflibercept on hypertension and to evaluate the beneficial effects of L-arg supplementation, we administered these two drugs to WT mice for up to 14 days (at an interval of two days). Long-term administration of aflibercept resulted in a sustained increase in BP and a severely impaired EDR, which are associated with NOX1/NOX4-mediated production of ROS, increase in ET-1, inhibition of AKT/eNOS/NO signaling and a decreased expression of cationic amino acid transporter (CAT-1). The effects caused by long-term administration were greatly attenuated by L-arg supplementation in a dose-dependent manner. We conclude that aflibercept leads to vascular dysfunction and hypertension by inhibiting CAT-1/AKT/eNOS/NO signaling, increasing ET-1, and activating NOX1/NOX4-mediated oxidative stress, which can be suppressed by supplementation of L-arg. Therefore, L-arg could be a potential therapeutic agent for aflibercept-induced hypertension.
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28
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Jin X, Kim WB, Kim MN, Jung WW, Kang HK, Hong EH, Kim YS, Shim WJ, Han HC, Colwell CS, Kim YB, Kim YI. Oestrogen inhibits salt-dependent hypertension by suppressing GABAergic excitation in magnocellular AVP neurons. Cardiovasc Res 2021; 117:2263-2274. [PMID: 32960965 PMCID: PMC10616626 DOI: 10.1093/cvr/cvaa271] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 06/24/2020] [Accepted: 09/08/2020] [Indexed: 12/25/2022] Open
Abstract
AIMS Abundant evidence indicates that oestrogen (E2) plays a protective role against hypertension. Yet, the mechanism underlying the antihypertensive effect of E2 is poorly understood. In this study, we sought to determine the mechanism through which E2 inhibits salt-dependent hypertension. METHODS AND RESULTS To this end, we performed a series of in vivo and in vitro experiments employing a rat model of hypertension that is produced by deoxycorticosterone acetate (DOCA)-salt treatment after uninephrectomy. We found that E2 prevented DOCA-salt treatment from inducing hypertension, raising plasma arginine-vasopressin (AVP) level, enhancing the depressor effect of the V1a receptor antagonist (Phenylac1,D-Tyr(Et)2,Lys6,Arg8,des-Gly9)-vasopressin, and converting GABAergic inhibition to excitation in hypothalamic magnocellular AVP neurons. Moreover, we obtained results indicating that the E2 modulation of the activity and/or expression of NKCC1 (Cl- importer) and KCC2 (Cl- extruder) underpins the effect of E2 on the transition of GABAergic transmission in AVP neurons. Lastly, we discovered that, in DOCA-salt-treated hypertensive ovariectomized rats, CLP290 (prodrug of the KCC2 activator CLP257, intraperitoneal injections) lowered blood pressure, and plasma AVP level and hyperpolarized GABA equilibrium potential to prevent GABAergic excitation from emerging in the AVP neurons of these animals. CONCLUSION Based on these results, we conclude that E2 inhibits salt-dependent hypertension by suppressing GABAergic excitation to decrease the hormonal output of AVP neurons.
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Affiliation(s)
- Xiangyan Jin
- Department of Physiology and Neuroscience Research Institute, Korea University College of Medicine, 126-1 Anam-dong 5-ga, Seoul 136-705, Republic of Korea
| | - Woong Bin Kim
- Department of Physiology and Neuroscience Research Institute, Korea University College of Medicine, 126-1 Anam-dong 5-ga, Seoul 136-705, Republic of Korea
| | - Mi-Na Kim
- Department of Internal Medicine, Cardiovascular Section, Korea University Anam Hospital, Seoul 136-705, Republic of Korea
| | - Won Woo Jung
- Department of Physiology and Neuroscience Research Institute, Korea University College of Medicine, 126-1 Anam-dong 5-ga, Seoul 136-705, Republic of Korea
| | - Hyung Kyung Kang
- Department of Physiology and Neuroscience Research Institute, Korea University College of Medicine, 126-1 Anam-dong 5-ga, Seoul 136-705, Republic of Korea
| | - Eun-Hwa Hong
- Department of Physiology and Neuroscience Research Institute, Korea University College of Medicine, 126-1 Anam-dong 5-ga, Seoul 136-705, Republic of Korea
| | - Yoon Sik Kim
- Department of Physiology and Neuroscience Research Institute, Korea University College of Medicine, 126-1 Anam-dong 5-ga, Seoul 136-705, Republic of Korea
| | - Wan Joo Shim
- Department of Internal Medicine, Cardiovascular Section, Korea University Anam Hospital, Seoul 136-705, Republic of Korea
| | - Hee Chul Han
- Department of Physiology and Neuroscience Research Institute, Korea University College of Medicine, 126-1 Anam-dong 5-ga, Seoul 136-705, Republic of Korea
| | - Christopher S Colwell
- Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, USA
| | - Young-Beom Kim
- Department of Physiology and Neuroscience Research Institute, Korea University College of Medicine, 126-1 Anam-dong 5-ga, Seoul 136-705, Republic of Korea
| | - Yang In Kim
- Department of Physiology and Neuroscience Research Institute, Korea University College of Medicine, 126-1 Anam-dong 5-ga, Seoul 136-705, Republic of Korea
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Choi YY, Kim A, Seong KM. Chronic radiation exposure aggravates atherosclerosis by stimulating neutrophil infiltration. Int J Radiat Biol 2021; 97:1270-1281. [PMID: 34032557 DOI: 10.1080/09553002.2021.1934750] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/07/2021] [Accepted: 05/18/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND Radiation exposure is known to increase the risk of chronic inflammatory diseases, such as atherosclerosis, by modulating inflammation. METHODS To investigate the infiltration of leukocytes in radiation-aggravated atherosclerosis, we examined low-density lipoprotein receptor-deficient (Ldlr-/-) mice and C57BL/6j mice after exposure to 0.5 or 1 Gy radiation over 16 weeks. RESULTS We found that radiation exposure induced atherosclerosis development in Ldlr-/- mice, as demonstrated by increased lipid-laden plaque size, reactive oxygen species levels, and levels of the pro-inflammatory cytokines, IL-1β and TNF-α, in the aortas and spleens. Total plasma cholesterol, triglyceride, and LDL cholesterol levels were also increased by radiation exposure, along with cardiovascular risk. We also showed dose-dependent increases in neutrophils and monocytes that coincided with a reduction in lymphocytes in the spleens of Ldlr-/- mice. The correlation between the infiltration of leukocytes and cytokine production was also confirmed in the hearts and spleens of these mice. CONCLUSIONS We concluded that chronic radiation exposure increased the production of pro-inflammatory mediators, which was associated with the migration of neutrophils and inflammatory monocytes into sites of atherosclerosis. Thus, our data suggest that the accumulation of neutrophils and inflammatory monocytes, together with the reduction of lymphocytes, contribute to aggravated atherosclerosis in Ldlr-/- mice under prolonged exposure to radiation.
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Affiliation(s)
- You Yeon Choi
- Laboratory of Biodosimetry, National Radiation Emergency Medical Center, KIRAMS, Seoul, Republic of Korea
| | - Areumnuri Kim
- Laboratory of Radiation Exposure and Therapeutics, National Radiation Emergency Medical Center, KIRAMS, Seoul, Republic of Korea
| | - Ki Moon Seong
- Laboratory of Biodosimetry, National Radiation Emergency Medical Center, KIRAMS, Seoul, Republic of Korea
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Ye X, Yi Q, Shao J, Zhang Y, Zha M, Yang Q, Xia W, Ye Z, Song P. Trends in Prevalence of Hypertension and Hypertension Phenotypes Among Chinese Children and Adolescents Over Two Decades (1991-2015). Front Cardiovasc Med 2021; 8:627741. [PMID: 34046436 PMCID: PMC8144307 DOI: 10.3389/fcvm.2021.627741] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 04/08/2021] [Indexed: 11/13/2022] Open
Abstract
Background: Hypertension is a leading cause of cardiovascular-related morbidity and mortality. Elevated blood pressure (BP) in children is related to long-term adverse health effects. Until recently, few studies have reported the secular trend and associated factors of hypertension phenotypes in Chinese children and adolescents. Methods: From the China Health and Nutrition Survey (CHNS) 1991-2015, a total of 15,143 records of children aged 7-17 years old were included. Following definitions of hypertension from the Chinese Child Blood Pressure References Collaborative Group, we estimated the prevalence of prehypertension, hypertension, stage 1 hypertension, stage 2 hypertension and its phenotypes (ISH, isolated systolic hypertension; IDH, isolated diastolic hypertension; SDH, combined systolic and diastolic hypertension). General estimation equation was used to analyze the trends in the prevalence of hypertension and hypertension phenotypes, and a multivariable logistic regression was constructed to explore the associated factors. Results: During 1991-2015, increasing trends were revealed in BP and hypertension prevalence (P < 0.001) in Chinese children and adolescents. For ISH, IDH and SDH, the age-standardized prevalence increased dramatically from 0.9 to 2.2%, from 6.2 to 14.1%, and from 1.4 to 2.9%, respectively (all P < 0.001). Adolescents aged 13-17 years (OR = 1.76, 95% CI: 1.56-1.97, P < 0.001), general obesity (OR = 2.69, 95% CI: 2.10-3.44, P < 0.001) and central obesity (OR = 1.49, 95% CI: 1.21-1.83, P < 0.001) were positively associated with hypertension, whereas the South region (OR = 0.65, 95% CI: 0.58-0.73, P < 0.001) was a negative factor. Furthermore, body mass index (BMI) and general obesity were linked to the presence of ISH, IDH and SDH. Age, waist circumference (WC) and central obesity were additionally associated with ISH, and sex, age, urban/rural setting, North/South region, WC and central obesity were additionally associated with IDH. Conclusion: BP levels and prevalence of hypertension and phenotypes increased dramatically in Chinese children and adolescents from 1991 to 2015. Regional discrepancy, demographic features, BMI, WC and overweight/obesity status were associated factors of hypertension among youths.
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Affiliation(s)
- Xinxin Ye
- School of Public Health, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
| | - Qian Yi
- School of Public Health, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
| | - Jing Shao
- School of Nursing, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
| | - Yan Zhang
- Faculty of Life Science and Medicine, Kings College London, London, United Kingdom
| | - Mingming Zha
- Medical School Southeast University, Nanjing, China
| | - Qingwen Yang
- Medical School Southeast University, Nanjing, China
| | - Wei Xia
- School of Nursing, Sun Yat-Sen University, Guangdong, China
| | - Zhihong Ye
- School of Nursing, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
| | - Peige Song
- School of Public Health, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.,Women's Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
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31
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Dama A, Baggio C, Boscaro C, Albiero M, Cignarella A. Estrogen Receptor Functions and Pathways at the Vascular Immune Interface. Int J Mol Sci 2021; 22:4254. [PMID: 33923905 PMCID: PMC8073008 DOI: 10.3390/ijms22084254] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 04/09/2021] [Accepted: 04/14/2021] [Indexed: 12/28/2022] Open
Abstract
Estrogen receptor (ER) activity mediates multiple physiological processes in the cardiovascular system. ERα and ERβ are ligand-activated transcription factors of the nuclear hormone receptor superfamily, while the G protein-coupled estrogen receptor (GPER) mediates estrogenic signals by modulating non-nuclear second messengers, including activation of the MAP kinase signaling cascade. Membrane localizations of ERs are generally associated with rapid, non-genomic effects while nuclear localizations are associated with nuclear activities/transcriptional modulation of target genes. Gender dependence of endothelial biology, either through the action of sex hormones or sex chromosome-related factors, is becoming increasingly evident. Accordingly, cardiometabolic risk increases as women transition to menopause. Estrogen pathways control angiogenesis progression through complex mechanisms. The classic ERs have been acknowledged to function in mediating estrogen effects on glucose metabolism, but 17β-estradiol also rapidly promotes endothelial glycolysis by increasing glucose transporter 1 (GLUT1) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) levels through GPER-dependent mechanisms. Estrogens alter monocyte and macrophage phenotype(s), and induce effects on other estrogen-responsive cell lineages (e.g., secretion of cytokines/chemokines/growth factors) that impact macrophage function. The pharmacological modulation of ERs for therapeutic purposes, however, is particularly challenging due to the lack of ER subtype selectivity of currently used agents. Identifying the determinants of biological responses to estrogenic agents at the vascular immune interface and developing targeted pharmacological interventions may result in novel improved therapeutic solutions.
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Affiliation(s)
- Aida Dama
- Department of Medicine, University of Padova, 35128 Padova, Italy; (A.D.); (M.A.)
| | - Chiara Baggio
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35128 Padova, Italy; (C.B.); (C.B.)
| | - Carlotta Boscaro
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35128 Padova, Italy; (C.B.); (C.B.)
| | - Mattia Albiero
- Department of Medicine, University of Padova, 35128 Padova, Italy; (A.D.); (M.A.)
- Venetian Institute of Molecular Medicine, 35129 Padova, Italy
| | - Andrea Cignarella
- Department of Medicine, University of Padova, 35128 Padova, Italy; (A.D.); (M.A.)
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X‑irradiation induces acute and early term inflammatory responses in atherosclerosis‑prone ApoE‑/‑ mice and in endothelial cells. Mol Med Rep 2021; 23:399. [PMID: 33786610 PMCID: PMC8025474 DOI: 10.3892/mmr.2021.12038] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 12/09/2020] [Indexed: 01/09/2023] Open
Abstract
Thoracic radiotherapy is an effective treatment for many types of cancer; however it is also associated with an increased risk of developing cardiovascular disease (CVD), appearing mainly ≥10 years after radiation exposure. The present study investigated acute and early term physiological and molecular changes in the cardiovascular system after ionizing radiation exposure. Female and male ApoE‑/‑ mice received a single exposure of low or high dose X‑ray thoracic irradiation (0.1 and 10 Gy). The level of cholesterol and triglycerides, as well as a large panel of inflammatory markers, were analyzed in serum samples obtained at 24 h and 1 month after irradiation. The secretion of inflammatory markers was further verified in vitro in coronary artery and microvascular endothelial cell lines after exposure to low and high dose of ionizing radiation (0.1 and 5 Gy). Local thoracic irradiation of ApoE‑/‑ mice increased serum growth differentiation factor‑15 (GDF‑15) and C‑X‑C motif chemokine ligand 10 (CXCL10) levels in both female and male mice 24 h after high dose irradiation, which were also secreted from coronary artery and microvascular endothelial cells in vitro. Sex‑specific responses were observed for triglyceride and cholesterol levels, and some of the assessed inflammatory markers as detailed below. Male ApoE‑/‑ mice demonstrated elevated intercellular adhesion molecule‑1 and P‑selectin at 24 h, and adiponectin and plasminogen activator inhibitor‑1 at 1 month after irradiation, while female ApoE‑/‑ mice exhibited decreased monocyte chemoattractant protein‑1 and urokinase‑type plasminogen activator receptor at 24 h, and basic fibroblast growth factor 1 month after irradiation. The inflammatory responses were mainly significant following high dose irradiation, but certain markers showed significant changes after low dose exposure. The present study revealed that acute/early inflammatory responses occurred after low and high dose thoracic irradiation. However, further research is required to elucidate early asymptomatic changes in the cardiovascular system post thoracic X‑irradiation and to investigate whether GDF‑15 and CXCL10 could be considered as potential biomarkers for the early detection of CVD risk in thoracic radiotherapy‑treated patients.
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Comparison of cardiorespiratory resistance in different menstrual cycle phases in female futsal players. APUNTS SPORTS MEDICINE 2021. [DOI: 10.1016/j.apunsm.2020.100341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Selective activation of the estrogen receptor-β by the polysaccharide from Cynanchum wilfordii alleviates menopausal syndrome in ovariectomized mice. Int J Biol Macromol 2020; 165:1029-1037. [PMID: 32991896 DOI: 10.1016/j.ijbiomac.2020.09.165] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 09/11/2020] [Accepted: 09/20/2020] [Indexed: 12/14/2022]
Abstract
The menopausal syndrome caused by rapid changes in hormone levels greatly influences the quality of life of women. Though hormone replacement therapy (HRT) is widely used to treat the menopausal syndrome, it exhibits many side effects, including the risk of thrombosis, cardiovascular diseases, and increased incidence of breast cancer; thus, diversifying the interest for phytotherapy-based materials as alternatives to HRT. Here, we isolated a crude polysaccharide fraction (CWPF) from Cynanchum wilfordii root that alleviated the ovariectomy-induced uterine atrophy and bone loss without changes in plasma estradiol concentration in mice. Increased plasma levels of follicle-stimulating hormone (FSH), alkaline phosphatase (ALP), osteocalcin (OC) in ovariectomized mice were also reduced to normal levels by CWPF administration. We found that the inhibitory effects of CWPF on menopausal symptoms were mediated by the estrogen receptor β (ER-β) specific activation, not ER-α. Moreover, CWPF treatment suppressed the phosphorylation of Akt, suggesting that CWPF alleviates post-menopausal symptoms by regulating ER-β related Akt signaling pathway. These results demonstrate that the polysaccharides corresponding to CWPF among the water-soluble extracts of CW could be used as a beneficial herbal alternative for the development of therapeutic agents to prevent menopausal syndrome in women.
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Gohar EY. G protein-coupled estrogen receptor 1 as a novel regulator of blood pressure. Am J Physiol Renal Physiol 2020; 319:F612-F617. [PMID: 32893662 DOI: 10.1152/ajprenal.00045.2020] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The mechanisms underlying hypertension are multifaceted and incompletely understood. New evidence suggests that G protein-coupled estrogen receptor 1 (GPER1) mediates protective actions within the cardiovascular and renal systems. This mini-review focuses on recent advancements in our understanding of the vascular, renal, and cardiac GPER1-mediated mechanisms that influence blood pressure regulation. We emphasize clinical and basic evidence that suggests GPER1 as a novel target to aid therapeutic strategies for hypertension. Furthermore, we discuss current controversies and challenges facing GPER1-related research.
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Affiliation(s)
- Eman Y Gohar
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
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Estrogen Receptors and Estrogen-Induced Uterine Vasodilation in Pregnancy. Int J Mol Sci 2020; 21:ijms21124349. [PMID: 32570961 PMCID: PMC7352873 DOI: 10.3390/ijms21124349] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 06/10/2020] [Accepted: 06/15/2020] [Indexed: 12/16/2022] Open
Abstract
Normal pregnancy is associated with dramatic increases in uterine blood flow to facilitate the bidirectional maternal–fetal exchanges of respiratory gases and to provide sole nutrient support for fetal growth and survival. The mechanism(s) underlying pregnancy-associated uterine vasodilation remain incompletely understood, but this is associated with elevated estrogens, which stimulate specific estrogen receptor (ER)-dependent vasodilator production in the uterine artery (UA). The classical ERs (ERα and ERβ) and the plasma-bound G protein-coupled ER (GPR30/GPER) are expressed in UA endothelial cells and smooth muscle cells, mediating the vasodilatory effects of estrogens through genomic and/or nongenomic pathways that are likely epigenetically modified. The activation of these three ERs by estrogens enhances the endothelial production of nitric oxide (NO), which has been shown to play a key role in uterine vasodilation during pregnancy. However, the local blockade of NO biosynthesis only partially attenuates estrogen-induced and pregnancy-associated uterine vasodilation, suggesting that mechanisms other than NO exist to mediate uterine vasodilation. In this review, we summarize the literature on the role of NO in ER-mediated mechanisms controlling estrogen-induced and pregnancy-associated uterine vasodilation and our recent work on a “new” UA vasodilator hydrogen sulfide (H2S) that has dramatically changed our view of how estrogens regulate uterine vasodilation in pregnancy.
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Aryan L, Younessi D, Zargari M, Banerjee S, Agopian J, Rahman S, Borna R, Ruffenach G, Umar S, Eghbali M. The Role of Estrogen Receptors in Cardiovascular Disease. Int J Mol Sci 2020; 21:ijms21124314. [PMID: 32560398 PMCID: PMC7352426 DOI: 10.3390/ijms21124314] [Citation(s) in RCA: 96] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Revised: 06/10/2020] [Accepted: 06/15/2020] [Indexed: 02/07/2023] Open
Abstract
Cardiovascular Diseases (CVDs) are the leading cause of death globally. More than 17 million people die worldwide from CVD per year. There is considerable evidence suggesting that estrogen modulates cardiovascular physiology and function in both health and disease, and that it could potentially serve as a cardioprotective agent. The effects of estrogen on cardiovascular function are mediated by nuclear and membrane estrogen receptors (ERs), including estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), and G-protein-coupled ER (GPR30 or GPER). Receptor binding in turn confers pleiotropic effects through both genomic and non-genomic signaling to maintain cardiovascular homeostasis. Each ER has been implicated in multiple pre-clinical cardiovascular disease models. This review will discuss current reports on the underlying molecular mechanisms of the ERs in regulating vascular pathology, with a special emphasis on hypertension, pulmonary hypertension, and atherosclerosis, as well as in regulating cardiac pathology, with a particular emphasis on ischemia/reperfusion injury, heart failure with reduced ejection fraction, and heart failure with preserved ejection fraction.
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Román G, Jackson R, Reis J, Román A, Toledo J, Toledo E. Extra-virgin olive oil for potential prevention of Alzheimer disease. Rev Neurol (Paris) 2019; 175:705-723. [DOI: 10.1016/j.neurol.2019.07.017] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Revised: 07/12/2019] [Accepted: 07/12/2019] [Indexed: 02/07/2023]
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Elliot S, Periera-Simon S, Xia X, Catanuto P, Rubio G, Shahzeidi S, El Salem F, Shapiro J, Briegel K, Korach KS, Glassberg MK. MicroRNA let-7 Downregulates Ligand-Independent Estrogen Receptor-mediated Male-Predominant Pulmonary Fibrosis. Am J Respir Crit Care Med 2019; 200:1246-1257. [PMID: 31291549 PMCID: PMC6857483 DOI: 10.1164/rccm.201903-0508oc] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Accepted: 07/10/2019] [Indexed: 12/26/2022] Open
Abstract
Rationale: The relevance of hormones in idiopathic pulmonary fibrosis (IPF), a predominantly male lung disease, is unknown.Objectives: To determine whether the ER (estrogen receptor) facilitates the development of pulmonary fibrosis and is mediated in part through microRNA regulation of ERα and ERα-activated profibrotic pathways.Methods: ER expression in male lung tissue and myofibroblasts from control subjects (n = 6) and patients with IPF (n = 6), aging bleomycin (BLM)-treated mice (n = 7), and BLM-treated AF2ERKI mice (n = 7) was determined. MicroRNAs that regulate ER and fibrotic pathways were assessed. Transfections with a reporter plasmid containing the 3' untranslated region of the gene encoding ERα (ESR1) with and without miRNA let-7 mimics or inhibitors or an estrogen response element-driven reporter construct (ERE) construct were conducted.Measurements and Main Results: ERα expression increased in IPF lung tissue, myofibroblasts, or BLM mice. In vitro treatment with let-7 mimic transfections in human myofibroblasts reduced ERα expression and associated fibrotic pathways. AF2ERKI mice developed BLM-induced lung fibrosis, suggesting a role for growth factors in stimulating ER and fibrosis. IGF-1 (insulin-like growth factor 1) expression was increased and induced a fourfold increase of an ERE construct.Conclusions: Our data show 1) a critical role for ER and let-7 in lung fibrosis, and 2) that IGF may stimulate ER in an E2-independent manner. These results underscore the role of sex steroid hormones and their receptors in diseases that demonstrate a sex prevalence, such as IPF.
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Affiliation(s)
| | | | - Xiaomei Xia
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, and
| | | | | | - Shahriar Shahzeidi
- Division of Pediatric Pulmonology, Department of Pediatrics, University of Miami Leonard M. Miller School of Medicine, Miami, Florida
| | - Fadi El Salem
- Icahn School of Medicine at Mount Sinai, New York, New York; and
| | - Josh Shapiro
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, and
| | | | - Kenneth S. Korach
- Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina
| | - Marilyn K. Glassberg
- Department of Surgery
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, and
- Division of Pediatric Pulmonology, Department of Pediatrics, University of Miami Leonard M. Miller School of Medicine, Miami, Florida
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Connelly PJ, Marie Freel E, Perry C, Ewan J, Touyz RM, Currie G, Delles C. Gender-Affirming Hormone Therapy, Vascular Health and Cardiovascular Disease in Transgender Adults. Hypertension 2019; 74:1266-1274. [PMID: 31656099 PMCID: PMC6887638 DOI: 10.1161/hypertensionaha.119.13080] [Citation(s) in RCA: 114] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Gender-affirming or cross-sex hormone therapy is integral to the management of transgender individuals yet our appreciation of the effects of such hormones on cardiovascular health is limited. Insights into vascular pathophysiology and outcomes in transgender people receiving sex steroids could be fundamental in providing better care for this population through the management of cardiovascular risk and more broadly advance our understanding of the role of sex and gender in vascular health and disease. In addition, there is a need to understand how gender-affirming hormone therapy impacts cardiovascular disease risk and events as transgender individuals age. This review explores the available evidence on the associations between gender-affirming hormones and cardiovascular events such as coronary artery disease, stroke, hypertension, thrombosis, lipid abnormalities, and diabetes mellitus. Current research about vascular outcomes in adults receiving hormonal therapy is limited by the absence of large cohort studies, lack of appropriate control populations, and inadequate data acquisition from gender identity services. Existing epidemiological data suggest that the use of estrogens in transgender females confers an increased risk of myocardial infarction and ischemic stroke. Conversely, transgender males receiving testosterone lack any consistent or convincing evidence of increased risk of cardiovascular or cerebrovascular disease. Further studies are required to confirm whether such risk exists and the mechanisms by which they occur.
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Affiliation(s)
- Paul J Connelly
- From the Institute of Cardiovascular and Medical Sciences, British Heart Foundation, Glasgow Cardiovascular Research Center, University of Glasgow, United Kingdom (P.J.C., E.M.F., C.P., R.M.T., G.C., C.D.)
| | - E Marie Freel
- From the Institute of Cardiovascular and Medical Sciences, British Heart Foundation, Glasgow Cardiovascular Research Center, University of Glasgow, United Kingdom (P.J.C., E.M.F., C.P., R.M.T., G.C., C.D.)
| | - Colin Perry
- From the Institute of Cardiovascular and Medical Sciences, British Heart Foundation, Glasgow Cardiovascular Research Center, University of Glasgow, United Kingdom (P.J.C., E.M.F., C.P., R.M.T., G.C., C.D.)
| | - John Ewan
- Sandyford Sexual Health Service, NHS Greater Glasgow and Clyde, Glasgow, United Kingdom (J.E.)
| | - Rhian M Touyz
- From the Institute of Cardiovascular and Medical Sciences, British Heart Foundation, Glasgow Cardiovascular Research Center, University of Glasgow, United Kingdom (P.J.C., E.M.F., C.P., R.M.T., G.C., C.D.)
| | - Gemma Currie
- From the Institute of Cardiovascular and Medical Sciences, British Heart Foundation, Glasgow Cardiovascular Research Center, University of Glasgow, United Kingdom (P.J.C., E.M.F., C.P., R.M.T., G.C., C.D.)
| | - Christian Delles
- From the Institute of Cardiovascular and Medical Sciences, British Heart Foundation, Glasgow Cardiovascular Research Center, University of Glasgow, United Kingdom (P.J.C., E.M.F., C.P., R.M.T., G.C., C.D.)
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Mishra JS, te Riele GM, Qi QR, Lechuga TJ, Gopalakrishnan K, Chen DB, Kumar S. Estrogen Receptor-β Mediates Estradiol-Induced Pregnancy-Specific Uterine Artery Endothelial Cell Angiotensin Type-2 Receptor Expression. Hypertension 2019; 74:967-974. [PMID: 31378106 PMCID: PMC6739159 DOI: 10.1161/hypertensionaha.119.13429] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Accepted: 07/01/2019] [Indexed: 01/05/2023]
Abstract
The pregnancy-augmented uterine vasodilation is linked to increased AT2R (angiotensin type-2 receptor) that mediates the vasodilatory effects of angiotensin II. However, the mechanisms controlling AT2R expression during pregnancy remain unclear. Estrogens are known to play a role in vascular adaptations during pregnancy. We hypothesized that estrogen stimulates uterine artery AT2R expression via ER (estrogen receptor)-β-dependent transcription in a pregnancy-specific endothelium-dependent manner. Plasma estradiol levels increased and peaked in late pregnancy and returned to prepregnant levels post-partum, correlating with uterine artery AT2R and ERβ upregulation. Estradiol stimulated AT2R mRNA expression in endothelium-intact but not endothelium-denuded late pregnant and nonpregnant rat uterine artery ex vivo. Consistently, estradiol stimulated AT2R mRNA expression in late pregnant but not nonpregnant primary human uterine artery endothelial cells in vitro, which was abolished by ER antagonist ICI 182,780. Higher ERα protein bound to ER-responsive elements in AT2R promoter in the nonpregnant arteries whereas higher ERβ bound in the pregnant state. ERα protein levels were similar but higher ERβ protein levels were expressed in pregnant versus nonpregnant human uterine artery endothelial cells. Estradiol stimulation recruited ERα to the AT2R promoter in the nonpregnant state and ERβ to the AT2R promoter in pregnancy; however, only ERβ recruitment mediated transactivation of the AT2R reporter gene in pregnant human uterine artery endothelial cells. Estradiol-induced AT2R expression was abolished by the specific ERβ (not ERα) antagonist 4-[2-Phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol (PHTPP) and mimicked by the specific ERβ (not ERα) agonist 2,3-bis(4-Hydroxyphenyl)-propionitrile (DPN) in pregnant human uterine artery endothelial cells in vitro. This study demonstrates a novel role of pregnancy-augmented ERβ in AT2R upregulation in the uterine artery and provides new insights into the mechanisms underlying uterine vascular adaptation to pregnancy.
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Affiliation(s)
- Jay S. Mishra
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Gigi M. te Riele
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Qian-Rong Qi
- Department of Obstetrics & Gynecology, University of California-Irvine, Irvine, CA 92697, USA
| | - Thomas J. Lechuga
- Department of Obstetrics & Gynecology, University of California-Irvine, Irvine, CA 92697, USA
| | - Kathirvel Gopalakrishnan
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Dong-bao Chen
- Department of Obstetrics & Gynecology, University of California-Irvine, Irvine, CA 92697, USA
| | - Sathish Kumar
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA
- Department of Obstetrics and Gynecology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA
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Manosroi W, Williams GH. Genetics of Human Primary Hypertension: Focus on Hormonal Mechanisms. Endocr Rev 2019; 40:825-856. [PMID: 30590482 PMCID: PMC6936319 DOI: 10.1210/er.2018-00071] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 09/07/2018] [Indexed: 02/06/2023]
Abstract
Increasingly, primary hypertension is being considered a syndrome and not a disease, with the individual causes (diseases) having a common sign-an elevated blood pressure. To determine these causes, genetic tools are increasingly employed. This review identified 62 proposed genes. However, only 21 of them met our inclusion criteria: (i) primary hypertension, (ii) two or more supporting cohorts from different publications or within a single publication or one supporting cohort with a confirmatory genetically modified animal study, and (iii) 600 or more subjects in the primary cohort; when including our exclusion criteria: (i) meta-analyses or reviews, (ii) secondary and monogenic hypertension, (iii) only hypertensive complications, (iv) genes related to blood pressure but not hypertension per se, (v) nonsupporting studies more common than supporting ones, and (vi) studies that did not perform a Bonferroni or similar multiassessment correction. These 21 genes were organized in a four-tiered structure: distant phenotype (hypertension); intermediate phenotype [salt-sensitive (18) or salt-resistant (0)]; subintermediate phenotypes under salt-sensitive hypertension [normal renin (4), low renin (8), and unclassified renin (6)]; and proximate phenotypes (specific genetically driven hypertensive subgroup). Many proximate hypertensive phenotypes had a substantial endocrine component. In conclusion, primary hypertension is a syndrome; many proposed genes are likely to be false positives; and deep phenotyping will be required to determine the utility of genetics in the treatment of hypertension. However, to date, the positive genes are associated with nearly 50% of primary hypertensives, suggesting that in the near term precise, mechanistically driven treatment and prevention strategies for the specific primary hypertension subgroups are feasible.
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Affiliation(s)
- Worapaka Manosroi
- Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.,Division of Endocrinology and Metabolism, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Gordon H Williams
- Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
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Bechmann N, Kniess T, Pietzsch J. Nitric Oxide-Releasing Selective Estrogen Receptor Modulators: A Bifunctional Approach to Improve the Therapeutic Index. J Med Chem 2019; 62:6525-6539. [DOI: 10.1021/acs.jmedchem.9b00171] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Nicole Bechmann
- Institute of Radiopharmaceutical Cancer Research, Department of Radiopharmaceutical and Chemical Biology, Helmholtz-Zentrum Dresden-Rossendorf, 01328 Dresden, Germany
| | - Torsten Kniess
- Institute of Radiopharmaceutical Cancer Research, Department of Radiopharmaceutical and Chemical Biology, Helmholtz-Zentrum Dresden-Rossendorf, 01328 Dresden, Germany
| | - Jens Pietzsch
- Institute of Radiopharmaceutical Cancer Research, Department of Radiopharmaceutical and Chemical Biology, Helmholtz-Zentrum Dresden-Rossendorf, 01328 Dresden, Germany
- School of Science, Faculty of Chemistry and Food Chemistry, Technische Universität Dresden, 01069 Dresden, Germany
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Hammes SR, Levin ER. Impact of estrogens in males and androgens in females. J Clin Invest 2019; 129:1818-1826. [PMID: 31042159 DOI: 10.1172/jci125755] [Citation(s) in RCA: 118] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Androgens and estrogens are known to be critical regulators of mammalian physiology and development. While these two classes of steroids share similar structures (in general, estrogens are derived from androgens via the enzyme aromatase), they subserve markedly different functions via their specific receptors. In the past, estrogens such as estradiol were thought to be most important in the regulation of female biology, while androgens such as testosterone and dihydrotestosterone were believed to primarily modulate development and physiology in males. However, the emergence of patients with deficiencies in androgen or estrogen hormone synthesis or actions, as well as the development of animal models that specifically target androgen- or estrogen-mediated signaling pathways, have revealed that estrogens and androgens regulate critical biological and pathological processes in both males and females. In fact, the concept of "male" and "female" hormones is an oversimplification of a complex developmental and biological network of steroid actions that directly impacts many organs. In this Review, we will discuss important roles of estrogens in males and androgens in females.
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Affiliation(s)
- Stephen R Hammes
- Division of Endocrinology and Metabolism, Department of Medicine, University of Rochester School of Medicine, Rochester, New York, USA
| | - Ellis R Levin
- Departments of Medicine and Biochemistry, UCI, Irvine, California, USA.,Division of Endocrinology, UCI and United States Department of Veterans Affairs Medical Center, Long Beach, California, USA
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Davis GK, Newsome AD, Cole AB, Ojeda NB, Alexander BT. Chronic Estrogen Supplementation Prevents the Increase in Blood Pressure in Female Intrauterine Growth-Restricted Offspring at 12 Months of Age. Hypertension 2019; 73:1128-1136. [PMID: 30929518 PMCID: PMC6458065 DOI: 10.1161/hypertensionaha.118.12379] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Accepted: 03/04/2019] [Indexed: 01/14/2023]
Abstract
Low birth weight is associated with a greater prevalence of hypertension and an earlier age at menopause in women in later life. Yet, the association between birth weight and blood pressure (BP) in women as they age is not well defined. In a rodent model of low birth weight induced by placental insufficiency, intrauterine growth restriction programs a significant increase in BP by 12 months of age in female growth-restricted offspring that is associated with early reproductive senescence, increased testosterone, and a shift in the hormonal milieu. Thus, this study tested the hypothesis that increased BP in female growth-restricted offspring is abolished by chronic estradiol supplementation. Placebo or 17β-estradiol valerate mini pellets (1.5 mg for 60-day release) were administered at 12 months of age for 6 weeks. BP, measured in conscious catheterized rats, was significantly increased in placebo-treated growth-restricted relative to placebo-treated control. However, BP was not elevated in estradiol-treated growth-restricted relative to placebo-treated growth-restricted. Estradiol mediates its effects on BP via its receptors and the renin-angiotensin system. BP was decreased in growth-restricted offspring treated with a G-protein coupled receptor agonist, G1 (400 mg/kg for 2 weeks). Renal AT1aR (angiotensin type 1a receptor) and AT1bR (angiotensin type 1b receptor) and renal AR (androgen receptor) mRNA expression were elevated in vehicle-treated growth-restricted offspring, but not in G1-treated growth-restricted. Therefore, these data suggest that chronic estradiol supplementation prevents the increase in BP that develops in female growth-restricted offspring via actions that may involve its G-protein coupled receptor and the renin-angiotensin system.
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Affiliation(s)
- Gwendolyn K. Davis
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson MS, 39216
| | - Ashley D. Newsome
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson MS, 39216
| | - Alyssa B. Cole
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson MS, 39216
| | - Norma B. Ojeda
- Department of Physiology and Pediatrics, University of Mississippi Medical Center, Jackson MS, 39216
| | - Barbara T. Alexander
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson MS, 39216
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The Protective Roles of Estrogen Receptor β in Renal Calcium Oxalate Crystal Formation via Reducing the Liver Oxalate Biosynthesis and Renal Oxidative Stress-Mediated Cell Injury. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:5305014. [PMID: 31178964 PMCID: PMC6501165 DOI: 10.1155/2019/5305014] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Revised: 11/06/2018] [Accepted: 11/15/2018] [Indexed: 11/18/2022]
Abstract
Females develop kidney stones less frequently than males do. However, it is unclear if this gender difference is related to altered estrogen/estrogen receptor (ER) signaling. Here, we found that ER beta (ERβ) signals could suppress hepatic oxalate biosynthesis via transcriptional upregulation of the glyoxylate aminotransferase (AGT1) expression. Results from multiple in vitro renal cell lines also found that ERβ could function via suppressing the oxalate-induced injury through increasing the reactive oxygen species (ROS) production that led to a decrease of the renal calcium oxalate (CaOx) crystal deposition. Mechanism study results showed that ERβ suppressed oxalate-induced oxidative stress via transcriptional suppression of the NADPH oxidase subunit 2 (NOX2) through direct binding to the estrogen response elements (EREs) on the NOX2 5′ promoter. We further applied two in vivo mouse models with glyoxylate-induced renal CaOx crystal deposition and one rat model with 5% hydroxyl-L-proline-induced renal CaOx crystal deposition. Our data demonstrated that mice lacking ERβ (ERβKO) as well as mice or rats treated with ERβ antagonist PHTPP had increased renal CaOx crystal deposition with increased urinary oxalate excretion and renal ROS production. Importantly, targeting ERβ-regulated NOX2 with the NADPH oxidase inhibitor, apocynin, can suppress the renal CaOx crystal deposition in the in vivo mouse model. Together, results from multiple in vitro cell lines and in vivo mouse/rat models all demonstrate that ERβ may protect against renal CaOx crystal deposition via inhibiting the hepatic oxalate biosynthesis and oxidative stress-induced renal injury.
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Nagai M, Förster CY, Dote K, Shimokawa H. Sex hormones in heart failure revisited? Eur J Heart Fail 2019; 21:308-310. [PMID: 30666765 DOI: 10.1002/ejhf.1408] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 12/03/2018] [Accepted: 12/04/2018] [Indexed: 11/06/2022] Open
Affiliation(s)
- Michiaki Nagai
- Department of Cardiology, Hiroshima City Asa Hospital, Hiroshima, Japan
| | - Carola Y Förster
- Department of Anaesthesiology and Critical Care, University Hospital Würzburg, Würzburg, Germany
| | - Keigo Dote
- Department of Cardiology, Hiroshima City Asa Hospital, Hiroshima, Japan
| | - Hiroaki Shimokawa
- Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
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Costa-Fraga FP, Goncalves GK, Souza-Neto FP, Reis AM, Capettini LA, Santos RA, Fraga-Silva RA, Stergiopulos N, da Silva RF. Age-related changes in vascular responses to angiotensin-(1-7) in female mice. J Renin Angiotensin Aldosterone Syst 2019; 19:1470320318789332. [PMID: 30024321 PMCID: PMC6053867 DOI: 10.1177/1470320318789332] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
The vasodilatory effect of angiotensin-(1-7) seems to vary between sexes, and estradiol (E2) can modulate the magnitude of the Ang-(1-7) vasodilatory response in female rats. However, there are few studies addressing the influence of sex on the age-related vasodilatory effect of Ang-(1-7). Here, we evaluated the vasodilatory response to Ang-(1-7) on vascular ageing. Ang-(1-7) dose-response curves were determined in mice aortic rings from males (old and young) and females (E2 treated/non-treated old and young) mounted in an isolated organ chamber. Abdominal aortic rings were used for protein expression analysis and determination of reactive oxygen species (ROS) and nitric oxide (NO) production. Our results showed that the Ang-(1-7) vasodilatory effect was absent in aorta from old females, contrasting with a full response in vessels from young females. The Ang-(1-7) vasodilatory effect was restored by E2 replacement in old females. A robust increase in Mas receptor, SOD2, NRF-2 and NOX2 expression was observed in aorta from old females, which was normalized by E2. This effect of E2 was also associated with lower production of ROS and normal levels of NO. In conclusion, our data demonstrated that pathways involved in the Ang-(1-7) vasodilatory response in female mice is affected by hormonal changes in ageing and rescued by E2.
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Affiliation(s)
- Fabiana P Costa-Fraga
- 1 Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Gleisy K Goncalves
- 2 Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Fernando P Souza-Neto
- 2 Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Adelina M Reis
- 2 Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Luciano As Capettini
- 2 Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Robson As Santos
- 2 Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Rodrigo A Fraga-Silva
- 1 Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Nikolaos Stergiopulos
- 1 Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Rafaela F da Silva
- 2 Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil
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49
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Mahmoodzadeh S, Dworatzek E. The Role of 17β-Estradiol and Estrogen Receptors in Regulation of Ca 2+ Channels and Mitochondrial Function in Cardiomyocytes. Front Endocrinol (Lausanne) 2019; 10:310. [PMID: 31156557 PMCID: PMC6529529 DOI: 10.3389/fendo.2019.00310] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Accepted: 04/30/2019] [Indexed: 11/13/2022] Open
Abstract
Numerous epidemiological, clinical, and animal studies showed that cardiac function and manifestation of cardiovascular diseases (CVDs) are different between males and females. The underlying reasons for these sex differences are definitely multifactorial, but major evidence points to a causal role of the sex steroid hormone 17β-estradiol (E2) and its receptors (ER) in the physiology and pathophysiology of the heart. Interestingly, it has been shown that cardiac calcium (Ca2+) ion channels and mitochondrial function are regulated in a sex-specific manner. Accurate mitochondrial function and Ca2+ signaling are of utmost importance for adequate heart function and crucial to maintaining the cardiovascular health. Due to the highly sensitive nature of these processes in the heart, this review article highlights the current knowledge regarding sex dimorphisms in the heart implicating the importance of E2 and ERs in the regulation of cardiac mitochondrial function and Ca2+ ion channels, thus the contractility. In particular, we provide an overview of in-vitro and in-vivo studies using either E2 deficiency; ER deficiency or selective ER activation, which suggest that E2 and ERs are strongly involved in these processes. In this context, this review also discusses the divergent E2-responses resulting from the activation of different ER subtypes in these processes. Detailed understanding of the E2 and ER-mediated molecular and cellular mechanisms in the heart under physiological and pathological conditions may help to design more specifically targeted drugs for the management of CVDs in men and women.
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Affiliation(s)
- Shokoufeh Mahmoodzadeh
- Department of Molecular Muscle Physiology, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
- *Correspondence: Shokoufeh Mahmoodzadeh
| | - Elke Dworatzek
- Department of Molecular Muscle Physiology, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
- Institute of Gender in Medicine, Charité Universitaetsmedizin, Berlin, Germany
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50
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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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