Sexual dimorphism in cardiac remodeling: the molecular mechanisms ruled by sex hormones in the heart

Sexual dimorphism refers to differences between biological sexes that extend beyond sexual characteristics. In humans, sexual dimorphism in the immune response has been well demonstrated, with females exhibiting lower infection rates than males for a variety of bacterial, viral, and parasitic pathogens. There is also a substantially increased incidence of autoimmune disease in females compared to males. Together, these trends indicate that females have a heightened immune reactogenicity to both self and non-self-molecular patterns. However, the molecular mechanisms driving the sexually dimorphic immune response are not fully understood. The female sex hormones estrogen and progesterone, as well as the male androgens, such as testosterone, elicit direct effects on the function and inflammatory capacity of immune cells. Several studies have identified a sex-specific transcriptome and methylome, independent of the well-described phenomenon of X-chromosome inactivation, suggesting that sexual dimorphism also occurs at the epigenetic level. Moreover, distinct alterations to the transcriptome and epigenetic landscape occur in synchrony with periods of hormonal change, such as puberty, pregnancy, menopause, and exogenous hormone therapy. These changes are also mirrored by changes in immune cell function. This review will outline the evidence for sex hormones and pregnancy-associated hormones as drivers of epigenetic change, and how this may contribute to the sexual dimorphism. Determining the effects of sex hormones on innate immune function is important for understanding sexually dimorphic autoimmune diseases, sex-specific responses to pathogens and vaccines, and how innate immunity is altered during periods of hormonal change (endogenous or exogenous).

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Regulatory Role of Sex Hormones in Cardiovascular Calcification

International Journal of Molecular Sciences ◽

10.3390/ijms22094620 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4620

Author(s):

Holly J. Woodward ◽

Dongxing Zhu ◽

Patrick W. F. Hadoke ◽

Victoria E. MacRae

Keyword(s):

Cardiovascular Disease ◽

Sex Differences ◽

Sexual Dimorphism ◽

Aortic Stenosis ◽

Sex Hormones ◽

Sex Hormone ◽

Increased Risk ◽

Male Sex ◽

Primary Male

Sex differences in cardiovascular disease (CVD), including aortic stenosis, atherosclerosis and cardiovascular calcification, are well documented. High levels of testosterone, the primary male sex hormone, are associated with increased risk of cardiovascular calcification, whilst estrogen, the primary female sex hormone, is considered cardioprotective. Current understanding of sexual dimorphism in cardiovascular calcification is still very limited. This review assesses the evidence that the actions of sex hormones influence the development of cardiovascular calcification. We address the current question of whether sex hormones could play a role in the sexual dimorphism seen in cardiovascular calcification, by discussing potential mechanisms of actions of sex hormones and evidence in pre-clinical research. More advanced investigations and understanding of sex hormones in calcification could provide a better translational outcome for those suffering with cardiovascular calcification.

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A bioinformatics approach for identifying potential molecular mechanisms and key genes involved in COVID-19 associated cardiac remodeling

Gene Reports ◽

10.1016/j.genrep.2021.101246 ◽

2021 ◽

pp. 101246

Author(s):

Hamid Ceylan

Keyword(s):

Cardiac Remodeling ◽

Molecular Mechanisms ◽

Key Genes

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NRSF-GNAO1-CaMK2 axis exacerbates cardiac remodeling and progresses heart failure by impairing Ca2+ homeostasis

European Heart Journal ◽

10.1093/ehjci/ehaa946.3672 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

H Inazumi ◽

K Kuwahara ◽

Y Kuwabara ◽

Y Nakagawa ◽

H Kinoshita ◽

...

Keyword(s):

Heart Failure ◽

Transgenic Mice ◽

Knockout Mice ◽

Cardiac Remodeling ◽

Cardiac Dysfunction ◽

Intracellular Signaling ◽

Molecular Mechanisms ◽

Systolic Function ◽

Dominant Negative Mutant ◽

Funding Source

Abstract Background In the development of heart failure, pathological intracellular signaling reactivates fetal cardiac genes, which leads to maladaptive remodeling and cardiac dysfunction. We previously reported that a transcriptional repressor, neuron restrictive silencer factor (NRSF) represses fetal cardiac genes and maintains normal cardiac function under normal conditions, while hypertrophic stimuli de-repress this NRSF mediated repression via activation of CaMKII. Molecular mechanisms by which NRSF maintains cardiac systolic function remains to be determined, however. Purpose To elucidate how NRSF maintains normal cardiac homeostasis and identify the novel therapeutic targets for heart failure. Methods and results We generated cardiac-specific NRSF knockout mice (NRSF cKO), and found that these NRSF cKO showed cardiac dysfunction and premature deaths accompanied with lethal arrhythmias, as was observed in our previously reported cardiac-specific dominant-negative mutant of NRSF transgenic mice (dnNRSF-Tg). By cDNA microarray analysis of dnNRSF-Tg and NRSF-cKO, we identified that expression of Gnao1 gene encoding Gαo, a member of inhibitory G proteins, was commonly increased in ventricles of both types of mice. ChIP-seq analysis, reporter assay and electrophoretic mobility shift assay identified that NRSF transcriptionally regulates Gnao1 gene expression. Genetic Knockdown of Gαo in dnNRSF-Tg and NRSF-cKO by crossing these mice with Gnao1 knockout mice ameliorated the reduced systolic function, increased arrhythmogenicity and reduced survival rates. Transgenic mice expressing a human GNAO1 in their hearts (GNAO1-Tg) showed progressive cardiac dysfunction with cardiac dilation. Ventricles obtained from GNAO1-Tg have increased phosphorylation level of CaMKII and increased expression level of endogenous mouse Gnao1 gene. These data suggest that increased cardiac expression of Gαo is sufficient to induce pathological Ca2+-dependent signaling and cardiac dysfunction, and that Gαo forms a positive regulatory circuit with CaMKII and NRSF. Electrophysiological analysis in ventricular myocytes of dnNRSF-Tg revealed that impaired Ca2+ handling via alterations in localized L-type calcium channel (LTCC) activities; decreased T-tubular and increased surface sarcolemmal LTCC activities, underlies Gαo-mediated cardiac dysfunction. Furthermore, we also identified increased expression of Gαo in ventricles of two different heart failure mice models, mice with transverse aortic constriction and mice carrying a mutant cardiac troponin T, and confirmed that genetic reduction of Gαo prevented the progression of cardiac dysfunction in both types of mice. Conclusions Increased expression of Gαo, induced by attenuation of NRSF-mediated repression forms a pathological circuit via activation of CaMKII. This circuit exacerbates cardiac remodeling and progresses heart failure by impairing Ca2+ homeostasis. Gαo is a potential therapeutic target for heart failure. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Grants-in –Aid for Scientific Research from the Japan Society for the Promotion of Science

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Sexual Dimorphisms of Adrenal Steroids, Sex Hormones, and Immunological Biomarkers and Possible Risk Factors for Developing Rheumatoid Arthritis

International Journal of Endocrinology ◽

10.1155/2015/929246 ◽

2015 ◽

Vol 2015 ◽

pp. 1-13 ◽

Cited By ~ 1

Author(s):

Alfonse T. Masi ◽

Azeem A. Rehman ◽

Laura C. Jorgenson ◽

Jennifer M. Smith ◽

Jean C. Aldag

Keyword(s):

Rheumatoid Arthritis ◽

Risk Factors ◽

Sexual Dimorphism ◽

Sex Hormones ◽

Inflammatory Diseases ◽

Interleukin 2 ◽

Tumor Necrosis Factor Receptor ◽

Serum Levels ◽

Amyloid A ◽

Neuroendocrine Factors

Innate immunity and immunological biomarkers are believed to be interrelated with sex hormones and other neuroendocrine factors. Sexual dimorphism mechanisms may be operating in certain rheumatic and inflammatory diseases which occur more frequently in women than men, as rheumatoid arthritis (RA). Less data have been available on altered interrelations of the combined neuroendocrine and immune (NEI) systems as risk factors for development of certain diseases. In this study, serological interrelations of NEI biomarkers are analyzed before symptomatic onset of RA (pre-RA) versus control (CN) subjects, stratified by sex. Sexual dimorphism was found in serum levels of acute serum amyloid A (ASAA), soluble interleukin-2 receptor alpha (sIL-2Rα), and soluble tumor necrosis factor receptor 1 (sTNF-R1). Multiple steroidal and hormonal (neuroendocrine) factors also showed highly(p<0.001)significant sexual dimorphism in their assayed values, but less for cortisol(p=0.012), and not for 17-hydroxyprogesterone(p=0.176). After stratification by sex and risk of developing RA, differential NEI correlational patterns were observed in the interplay of the NEI systems between the pre-RA and CN groups, which deserve further investigation.

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Sex differences in white adipose tissue expansion: emerging molecular mechanisms

Clinical Science ◽

10.1042/cs20210086 ◽

2021 ◽

Vol 135 (24) ◽

pp. 2691-2708

Author(s):

Simon T. Bond ◽

Anna C. Calkin ◽

Brian G. Drew

Keyword(s):

Sex Differences ◽

Sexual Dimorphism ◽

Gene Networks ◽

Large Scale ◽

Molecular Mechanisms ◽

Association Studies ◽

Tissue Expansion ◽

Economic Systems ◽

Genomic Association ◽

Males And Females

Abstract The escalating prevalence of individuals becoming overweight and obese is a rapidly rising global health problem, placing an enormous burden on health and economic systems worldwide. Whilst obesity has well described lifestyle drivers, there is also a significant and poorly understood component that is regulated by genetics. Furthermore, there is clear evidence for sexual dimorphism in obesity, where overall risk, degree, subtype and potential complications arising from obesity all differ between males and females. The molecular mechanisms that dictate these sex differences remain mostly uncharacterised. Many studies have demonstrated that this dimorphism is unable to be solely explained by changes in hormones and their nuclear receptors alone, and instead manifests from coordinated and highly regulated gene networks, both during development and throughout life. As we acquire more knowledge in this area from approaches such as large-scale genomic association studies, the more we appreciate the true complexity and heterogeneity of obesity. Nevertheless, over the past two decades, researchers have made enormous progress in this field, and some consistent and robust mechanisms continue to be established. In this review, we will discuss some of the proposed mechanisms underlying sexual dimorphism in obesity, and discuss some of the key regulators that influence this phenomenon.

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Skeletal Muscle Wasting: The Estrogen Side of Sexual Dimorphism

AJP Cell Physiology ◽

10.1152/ajpcell.00333.2021 ◽

2021 ◽

Author(s):

Shawna L. McMillin ◽

Everett C. Minchew ◽

Dawn A. Lowe ◽

Espen E. Spangenburg

Keyword(s):

Sex Differences ◽

Sexual Dimorphism ◽

Molecular Mechanisms ◽

Muscle Wasting ◽

Physiological Mechanisms ◽

Skeletal Muscle Wasting ◽

Muscle Biology ◽

Experimental Approaches ◽

The Impact ◽

Equal Efficacy

The importance of defining sex differences across various biological and physiological mechanisms is more pervasive now than it has been over the last 15-20 years. As the muscle biology field pushes to identify small molecules and interventions to prevent, attenuate or even reverse muscle wasting, we must consider the effect of sex as a biological variable. It should not be assumed that a therapeutic will affect males and females with equal efficacy or equivalent target affinities under conditions where muscle wasting is observed. With that said, it is not surprising to find that we have an unclear or even a poor understanding of the effects of sex or sex hormones on muscle wasting conditions. Although recent investigations are beginning to establish experimental approaches that will allow investigators to assess the impact of sex-specific hormones on muscle wasting, the field still has not established enough published scientific tools that will allow the field to rigorously address critical hypotheses. Thus, the purpose of this review is to assemble a current summary of knowledge in the area of sexual dimorphism driven by estrogens with an effort to provide insights to interested physiologists on necessary considerations when trying to assess models for potential sex differences in cellular and molecular mechanisms of muscle wasting.

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CBMT-45. SEX-SPECIFIC METABOLIC ADAPTIONS IN GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noz175.167 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi42-vi43

Author(s):

Jasmin Sponagel ◽

Shanshan Zhang ◽

Prakash Chinnaiyan ◽

Joshua Rubin ◽

Joseph Ippolito

Keyword(s):

Sex Differences ◽

Sexual Dimorphism ◽

Molecular Mechanisms ◽

Treatment Strategies ◽

Tca Cycle ◽

Metabolic Reprogramming ◽

Mitochondrial Activity ◽

Male And Female ◽

Glutamine Deprivation ◽

Novel Treatment Strategies

Abstract Glioblastoma (GBM) is the most common and aggressive brain tumor in adults. GBM occurs more commonly in males, but female patients survive significantly longer. Understanding the molecular mechanisms that underlie those sex differences could support novel treatment strategies. In this regard, we found that male and female GBM patient samples differ in their metabolite abundance and that male patients exhibit a significantly higher abundance of TCA cycle metabolites. We confirmed those findings in a murine model of GBM, which has previously yielded important insights into sexual dimorphism in GBM. Strikingly, sex differences in TCA cycle flux were entirely driven by glutamine flux, not glucose flux, suggesting a sex-specific role for glutamine in GBM. Metabolic manipulation through glutamine deprivation resulted in a greater growth inhibition in male GBM cells. Glutamine itself can be utilized for anabolic reactions or it can be converted to glutamate by glutaminase. Only male GBM cells were sensitive to pharmacological glutaminase inhibition with BPTES or CB-839, suggesting that male GBM cells are glutamate dependent while female GBM cells are not. Concordantly, we found significantly higher glutaminase levels in male GBM cells. Furthermore, we found that numerous metabolites (including NADH, ATP, and glutathione) involved in cellular processes downstream of glutamate were more abundant in male GBM cells. In contrast, female GBM cells were resistant to low glutamine conditions and glutaminase inhibitors unless glutamine-synthase activity was disrupted, suggesting that glutamine synthesis might play a more prominent role in female GBM. Together, these data indicate that male and female GBM differ in their metabolic adaptions. Male GBM utilize glutamate to fuel the TCA cycle and mitochondrial activity while female GBM synthesize and utilize glutamine itself. This sexual dimorphism in metabolic reprogramming reveals novel sex specific metabolic targets for GBM and underlines the importance of considering sex in metabolic targeting approaches.

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