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      Sex Differences in Proatherogenic Cytokine Levels

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          Abstract

          Background: It has been shown that sex affects immunity, including cytokine production. Given that atherosclerosis is an inflammatory disease promoted by specific cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, we aimed at evaluating whether sex could affect the levels of these proatherogenic cytokines in a group of healthy adults. In this analysis, we also included other cytokines and peptides that have been implicated in atherosclerosis development and progression. Methods: A total of 104 healthy adults were recruited; we measured circulating levels of IL-1β, IL-6, TNF-α, angiotensins and angiotensin-converting enzyme-2 (ACE2), as well as osteoprotegerin and receptor activator of nuclear factor κB ligand (RANKL). Results: IL-1β, IL-6, and TNF-α were significantly higher in men as compared to women. They were all associated with testosterone and the testosterone/estradiol ratio. They remained significantly associated with sex (but not with hormones) after being tested for potential confounders. Conclusions: Sex seems to influence the levels of proatherogenic cytokines. This is consistent not only with sex differences in vulnerability to infections but also with the higher cardiovascular risk exhibited by the male gender as compared to the female gender. Nevertheless, this association is only partly explained by hormone levels.

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          Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System

          ACE2 (angiotensin-converting enzyme 2) has a multiplicity of physiological roles that revolve around its trivalent function: a negative regulator of the renin-angiotensin system, facilitator of amino acid transport, and the severe acute respiratory syndrome-coronavirus (SARS-CoV) and SARS-CoV-2 receptor. ACE2 is widely expressed, including, in the lungs, cardiovascular system, gut, kidneys, central nervous system, and adipose tissue. ACE2 has recently been identified as the SARS-CoV-2 receptor, the infective agent responsible for coronavirus disease 2019, providing a critical link between immunity, inflammation, ACE2, and cardiovascular disease. Although sharing a close evolutionary relationship with SARS-CoV, the receptor-binding domain of SARS-CoV-2 differs in several key amino acid residues, allowing for stronger binding affinity with the human ACE2 receptor, which may account for the greater pathogenicity of SARS-CoV-2. The loss of ACE2 function following binding by SARS-CoV-2 is driven by endocytosis and activation of proteolytic cleavage and processing. The ACE2 system is a critical protective pathway against heart failure with reduced and preserved ejection fraction including, myocardial infarction and hypertension, and against lung disease and diabetes mellitus. The control of gut dysbiosis and vascular permeability by ACE2 has emerged as an essential mechanism of pulmonary hypertension and diabetic cardiovascular complications. Recombinant ACE2, gene-delivery of Ace2, Ang 1–7 analogs, and Mas receptor agonists enhance ACE2 action and serve as potential therapies for disease conditions associated with an activated renin-angiotensin system. rhACE2 (recombinant human ACE2) has completed clinical trials and efficiently lowered or increased plasma angiotensin II and angiotensin 1-7 levels, respectively. Our review summarizes the progress over the past 20 years, highlighting the critical role of ACE2 as the novel SARS-CoV-2 receptor and as the negative regulator of the renin-angiotensin system, together with implications for the coronavirus disease 2019 pandemic and associated cardiovascular diseases.
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            COVID-19: the gendered impacts of the outbreak

            Policies and public health efforts have not addressed the gendered impacts of disease outbreaks. 1 The response to coronavirus disease 2019 (COVID-19) appears no different. We are not aware of any gender analysis of the outbreak by global health institutions or governments in affected countries or in preparedness phases. Recognising the extent to which disease outbreaks affect women and men differently is a fundamental step to understanding the primary and secondary effects of a health emergency on different individuals and communities, and for creating effective, equitable policies and interventions. Although sex-disaggregated data for COVID-19 show equal numbers of cases between men and women so far, there seem to be sex differences in mortality and vulnerability to the disease. 2 Emerging evidence suggests that more men than women are dying, potentially due to sex-based immunological 3 or gendered differences, such as patterns and prevalence of smoking. 4 However, current sex-disaggregated data are incomplete, cautioning against early assumptions. Simultaneously, data from the State Council Information Office in China suggest that more than 90% of health-care workers in Hubei province are women, emphasising the gendered nature of the health workforce and the risk that predominantly female health workers incur. 5 The closure of schools to control COVID-19 transmission in China, Hong Kong, Italy, South Korea, and beyond might have a differential effect on women, who provide most of the informal care within families, with the consequence of limiting their work and economic opportunities. Travel restrictions cause financial challenges and uncertainty for mostly female foreign domestic workers, many of whom travel in southeast Asia between the Philippines, Indonesia, Hong Kong, and Singapore. 6 Consideration is further needed of the gendered implications of quarantine, such as whether women and men's different physical, cultural, security, and sanitary needs are recognised. Experience from past outbreaks shows the importance of incorporating a gender analysis into preparedness and response efforts to improve the effectiveness of health interventions and promote gender and health equity goals. During the 2014–16 west African outbreak of Ebola virus disease, gendered norms meant that women were more likely to be infected by the virus, given their predominant roles as caregivers within families and as front-line health-care workers. 7 Women were less likely than men to have power in decision making around the outbreak, and their needs were largely unmet. 8 For example, resources for reproductive and sexual health were diverted to the emergency response, contributing to a rise in maternal mortality in a region with one of the highest rates in the world. 9 During the Zika virus outbreak, differences in power between men and women meant that women did not have autonomy over their sexual and reproductive lives, 10 which was compounded by their inadequate access to health care and insufficient financial resources to travel to hospitals for check-ups for their children, despite women doing most of the community vector control activities. 11 Given their front-line interaction with communities, it is concerning that women have not been fully incorporated into global health security surveillance, detection, and prevention mechanisms. Women's socially prescribed care roles typically place them in a prime position to identify trends at the local level that might signal the start of an outbreak and thus improve global health security. Although women should not be further burdened, particularly considering much of their labour during health crises goes underpaid or unpaid, incorporating women's voices and knowledge could be empowering and improve outbreak preparedness and response. Despite the WHO Executive Board recognising the need to include women in decision making for outbreak preparedness and response, 12 there is inadequate women's representation in national and global COVID-19 policy spaces, such as in the White House Coronavirus Task Force. 13 © 2020 Miguel Medina/Contributor/Getty Images 2020 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. If the response to disease outbreaks such as COVID-19 is to be effective and not reproduce or perpetuate gender and health inequities, it is important that gender norms, roles, and relations that influence women's and men's differential vulnerability to infection, exposure to pathogens, and treatment received, as well as how these may differ among different groups of women and men, are considered and addressed. We call on governments and global health institutions to consider the sex and gender effects of the COVID-19 outbreak, both direct and indirect, and conduct an analysis of the gendered impacts of the multiple outbreaks, incorporating the voices of women on the front line of the response to COVID-19 and of those most affected by the disease within preparedness and response policies or practices going forward.
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              Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin–angiotensin–aldosterone inhibitors

              Abstract Aims The current pandemic coronavirus SARS-CoV-2 infects a wide age group but predominantly elderly individuals, especially men and those with cardiovascular disease. Recent reports suggest an association with use of renin–angiotensin–aldosterone system (RAAS) inhibitors. Angiotensin-converting enzyme 2 (ACE2) is a functional receptor for coronaviruses. Higher ACE2 concentrations might lead to increased vulnerability to SARS-CoV-2 in patients on RAAS inhibitors. Methods and results We measured ACE2 concentrations in 1485 men and 537 women with heart failure (index cohort). Results were validated in 1123 men and 575 women (validation cohort). The median age was 69 years for men and 75 years for women. The strongest predictor of elevated concentrations of ACE2 in both cohorts was male sex (estimate = 0.26, P < 0.001; and 0.19, P < 0.001, respectively). In the index cohort, use of ACE inhibitors, angiotensin receptor blockers (ARBs), or mineralocorticoid receptor antagonists (MRAs) was not an independent predictor of plasma ACE2. In the validation cohort, ACE inhibitor (estimate = –0.17, P = 0.002) and ARB use (estimate = –0.15, P = 0.03) were independent predictors of lower plasma ACE2, while use of an MRA (estimate = 0.11, P = 0.04) was an independent predictor of higher plasma ACE2 concentrations. Conclusion In two independent cohorts of patients with heart failure, plasma concentrations of ACE2 were higher in men than in women, but use of neither an ACE inhibitor nor an ARB was associated with higher plasma ACE2 concentrations. These data might explain the higher incidence and fatality rate of COVID-19 in men, but do not support previous reports suggesting that ACE inhibitors or ARBs increase the vulnerability for COVID-19 through increased plasma ACE2 concentrations.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                29 May 2020
                June 2020
                : 21
                : 11
                : 3861
                Affiliations
                [1 ]Department of Medical, Surgical, and Health Sciences, University of Trieste, Cattinara Teaching Hospital UCO Medicina Clinica, 34100 Trieste, Italy; effe.tonon@ 123456gmail.com (F.T.); morefrancica@ 123456gmail.com (M.F.); campagnoloelena@ 123456gmail.com (E.C.); tomferretti@ 123456yahoo.com (T.F.); sarah.comar@ 123456studenti.units.it (S.C.); fgiudici@ 123456units.it (F.G.); b.fabris@ 123456fmc.units.it (B.F.)
                [2 ]ASUGI Azienda Sanitaria Universitaria Integrata di Trieste, Cattinara Teaching Hospital, UCO Medicina Clinica, 34100 Trieste, Italy
                [3 ]Institute for Maternal and Child Health, IRCCS Burlo Garofolo, 34100 Trieste, Italy; barbaratoffoli.ts@ 123456gmail.com
                [4 ]Department of Life Sciences, University of Trieste, 34100 Trieste, Italy
                [5 ]Unit of Biostatistics, Epidemiology and Public Health, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua, 35100 Padova, Italy
                [6 ]Department of Diagnostics, Azienda USL Toscana Nordovest, 57100 Livorno, Italy; elisabetta.stenner@ 123456uslnordovest.toscana.it
                Author notes
                [* ]Correspondence: stella.bernardi@ 123456asuits.sanita.fvg.it ; Tel.: +39-040-399-4318
                Author information
                https://orcid.org/0000-0002-7429-3075
                https://orcid.org/0000-0002-6854-5782
                Article
                ijms-21-03861
                10.3390/ijms21113861
                7311959
                32485823
                4e0cf59e-0afd-4619-b5b2-8bc46d233087
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 29 April 2020
                : 27 May 2020
                Categories
                Article

                Molecular biology
                sex,gender,cytokines,inflammation,atherosclerosis,il-1β,il-6,tnf-α,opg,ace2,healthy adults
                Molecular biology
                sex, gender, cytokines, inflammation, atherosclerosis, il-1β, il-6, tnf-α, opg, ace2, healthy adults

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