The Zebrafish (Danio rerio) Is a Relevant Model for Studying Sex-Specific Effects of 17β-Estradiol in the Adult Heart

Cardiovascular diseases are a major cause of morbidity and mortality, and there are significant sex differences therein. However, the underlying mechanisms are poorly understood. The steroid hormone 17β-estradiol (E2) is thought to play a major role in cardiovascular sex differences and to be protective, but this may not hold true for males. We aimed at assessing whether the zebrafish is an appropriate model for the study of E2 effects in the heart. We hypothesized that E2 regulates the cardiac contractility of adult zebrafish in a sex-specific manner. Male and female zebrafish were treated with vehicle (control) or E2 and the cardiac contractility was measured 0, 4, 7 and 14 days after treatment initiation using echocardiography. There was no significant effect on the heart rate by E2. Notably, there was a significant decrease in the ejection fraction of male zebrafish treated with E2 compared with controls. By contrast, there was no major difference in the ejection fraction between the two female groups. The dramatic effect in male zebrafish occurred as early as 4 days post treatment initiation. Although there was no significant difference in stroke volume and cardiac output between the two male groups, these were significantly higher in female zebrafish treated with E2 compared with controls. Gene expression analysis revealed that the levels of estrogen receptors were comparable among all groups. In conclusion, our data demonstrate that the adult zebrafish heart robustly responds to E2 and this occurs in a sex-specific manner. Given the benefits of using zebrafish as a model, new targets may be identified for the development of novel cardiovascular therapies for male and female patients. This would contribute towards the realization of personalized medicine

Editorial : New Insights into Estrogen/Estrogen Receptor Effects in the Cardiac and Skeletal Muscle

Funding Information: We thank the authors of this Research Topic for their contributions and the reviewers for their evaluations. Funding. DL acknowledges support from the National Institutes of Health (R01AG031743 and R01AG062899). GK acknowledges support from the DZHK (German Centre for Cardiovascular Research) and the BMBF (German Ministry for Education and Research)

Estrogen-related mechanisms in sex differences of hypertension and target organ damage

GK acknowledges support from the DZHK (German Centre for Cardiovascular Research) and the BMBF (German Ministry for Education and Research). Publisher Copyright: © 2020 The Author(s).Hypertension (HTN) is a primary risk factor for cardiovascular (CV) events, target organ damage (TOD), premature death and disability worldwide. The pathophysiology of HTN is complex and influenced by many factors including biological sex. Studies show that the prevalence of HTN is higher among adults aged 60 and over, highlighting the increase of HTN after menopause in women. Estrogen (E2) plays an important role in the development of systemic HTN and TOD, exerting several modulatory effects. The influence of E2 leads to alterations in mechanisms regulating the sympathetic nervous system, renin-angiotensin-aldosterone system, body mass, oxidative stress, endothelial function and salt sensitivity; all associated with a crucial inflammatory state and influenced by genetic factors, ultimately resulting in cardiac, vascular and renal damage in HTN. In the present article, we discuss the role of E2 in mechanisms accounting for the development of HTN and TOD in a sex-specific manner. The identification of targets with therapeutic potential would contribute to the development of more efficient treatments according to individual needs.Peer reviewe

Menopause-Related Estrogen Decrease and the Pathogenesis of HFpEF : JACC Review Topic of the Week

Publisher Copyright: © 2020 American College of Cardiology FoundationHeart failure (HF) is a complex condition affecting >40 million people worldwide. It is defined by failure of the heart to pump (HF with reduced ejection fraction) or by the failure of the heart to relax, resulting in reduced filling but with preserved ejection fraction (HFpEF). HFpEF affects approximately 50% of patients with HF, most of whom are women. Given that the annual mortality ranges from 10% to 30% and as there are no treatments specifically directed for HFpEF, there is a need for better understanding of the underlying mechanisms of this condition. We put forward the hypothesis that the decline of estrogen at menopause might contribute to the pathogenesis of HFpEF and we highlight potential underlying mechanisms of estrogen action, which may attenuate the development of HFpEF. We also discuss areas in which additional research is needed to develop new approaches for prevention and treatment of HFpEF.Peer reviewe

Reduction of apoptosis and preservation of mitochondrial integrity under ischemia/reperfusion injury is mediated by estrogen receptor β

Background Estrogen improves cardiac recovery after ischemia/reperfusion (I/R) by yet incompletely understood mechanisms. Mitochondria play a crucial role in I/R injury through cytochrome c-dependent apoptosis activation. We tested the hypothesis that 17β-estradiol (E2) as well as a specific ERβ agonist improve cardiac recovery through estrogen receptor (ER)β-mediated mechanisms by reducing mitochondria-induced apoptosis and preserving mitochondrial integrity. Methods We randomized ovariectomized C57BL/6N mice 24h before I/R to pre-treatment with E2 or a specific ERβ agonist (ERβA). Isolated hearts were perfused for 20min prior to 30min global ischemia followed by 40min reperfusion. Results Compared with controls, ERβA and E2 treated groups showed a significant improvement in cardiac recovery, i.e. an increase in left ventricular developed pressure, dP/dtmax and dP/dtmin. ERβA and E2 pre- treatment led to a significant reduction in apoptosis with decreased cytochrome c release from the mitochondria and increased mitochondrial levels of anti-apoptotic Bcl2 and ACAA2. Protein levels of mitochondrial translocase inner membrane (TIM23) and mitochondrial complex I of respiratory chain were increased by ERβA and E2 pre-treatment. Furthermore, we found a significant increase of myosin light chain 2 (MLC2) phosphorylation together with ERK1/2 activation in E2, but not in ERβA treated groups. Conclusions Activation of ERβ is essential for the improvement of cardiac recovery after I/R through the inhibition of apoptosis and preservation of mitochondrial integrity and can be a achieved by a specific ERβ agonist. Furthermore, E2 modulates MLC2 activation after I/R independent of ERβ

Correction: Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy

This corrects the article DOI: 10.1371/journal.pone.017299

a web-based interactive knowledge-sharing platform for sex- and gender- specific medical education

Background Sex and Gender Medicine is a novel discipline that provides equitable medical care for society and improves outcomes for both male and female patients. The integration of sex- and gender-specific knowledge into medical curricula is limited due to adequate learning material, systematic teacher training and an innovative communication strategy. We aimed at initiating an e-learning and knowledge-sharing platform for Sex and Gender Medicine, the eGender platform (http://egender.charite.de), to ensure that future doctors and health professionals will have adequate knowledge and communication skills on sex and gender differences in order to make informed decisions for their patients. Methods The web-based eGender knowledge-sharing platform was designed to support the blended learning pedagogical teaching concept and follows the didactic concept of constructivism. Learning materials developed by Sex and Gender Medicine experts of seven universities have been used as the basis for the new learning tools. The content of these tools is patient-centered and provides add-on information on gender-sensitive aspects of diseases. The structural part of eGender was designed and developed using the open source e-learning platform Moodle. The eGender platform comprises an English and a German version of e-learning modules: one focusing on basic knowledge and seven on specific medical disciplines. Each module consists of several courses corresponding to a disease or symptom complex. Self-organized learning has to be managed by using different learning tools, e.g., texts and audiovisual material, tools for online communication and collaborative work. Results More than 90 users from Europe registered for the eGender Medicine learning modules. The most frequently accessed module was “Gender Medicine—Basics” and the users favored discussion forums. These e-learning modules fulfill the quality criteria for higher education and are used within the elective Master Module “Gender Medicine—Basics” implemented into the accredited Master of Public Health at Charité—Berlin. Conclusions The eGender platform is a flexible and user-friendly electronical knowledge-sharing platform providing evidence-based high-quality learning material used by a growing number of registered users. The eGender Medicine learning modules could be key in the reform of medical curricula to integrate Sex and Gender Medicine into the education of health professionals

Assessment of Bones Deficient in Fibrillin-1 Microfibrils Reveals Pronounced Sex Differences.

Defects in the extracellular matrix protein fibrillin-1 that perturb transforming growth factor beta (TGFβ) bioavailability lead to Marfan syndrome (MFS). MFS is an autosomal-dominant disorder, which is associated with connective tissue and skeletal defects, among others. To date, it is unclear how biological sex impacts the structural and functional properties of bone in MFS. The aim of this study was to investigate the effects of sex on bone microarchitecture and mechanical properties in mice with deficient fibrillin-1, a model of human MFS. Bones of 11-week-old male and female Fbn1mgR/mgR mice were investigated. Three-dimensional micro-computed tomography of femora and vertebrae revealed a lower ratio of trabecular bone volume to tissue volume, reduced trabecular number and thickness, and greater trabecular separation in females vs. males. Three-point bending of femora revealed significantly lower post-yield displacement and work-to-fracture in females vs. males. Mechanistically, we found higher Smad2 and ERK1/2 phosphorylation in females vs. males, demonstrating a greater activation of TGFβ signaling in females. In summary, the present findings show pronounced sex differences in the matrix and function of bones deficient in fibrillin-1 microfibrils. Consequently, sex-specific analysis of bone characteristics in patients with MFS may prove useful in improving the clinical management and life quality of these patients, through the development of sex-specific therapeutic approaches

Why the study of the effects of biological sex is important

Biological sex significantly affects the presentation, outcome of treatment and progression of disease. However, the role of sex has yet underestimated consequences for physiology and pathology. We put forward that a better understanding of the effects of sex in pathophysiology and the underlying mechanisms is necessary. This may facilitate the identification of targets that respond to specific therapies, thereby contributing towards a more appropriate and individualised medical care for both men and women