Molecular Mechanisms of Stress Signaling in the Female Heart

女性心脏压力信号的分子机制

• 批准号: 10548742
• 负责人: Diana Cruz Topete
• 金额: $ 13.88万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10548742
• 关键词: Affect; Age; Age Years; American; Apoptosis; Apoptotic; Binding; Biological Assay; Cardiac; Cardiac Myocytes; Cardiac health; Cardiovascular system; Caspase; Cause of Death; Cell Death; Cell membrane; Cells; Cessation of life; Clinical Trials; Complex; Cytochromes; Cytoplasm; Data; Disease; Elements; Estrogen Nuclear Receptor; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Exposure to; Female; Flow Cytometry; Funding; Funding Mechanisms; GRP gene; Gender; Gene Expression; Genes; Genetic Polymorphism; Genetic Transcription; Genomics; Genus Hippocampus; Glucocorticoid Receptor; Glucocorticoids; Goals; Gonadal Steroid Hormones; Grant; Health; Heart; Heart Diseases; Heart failure; Hormone Receptor; Hormones; Human; Hypoxia; In Situ Nick-End Labeling; Incidence; Incubated; Infarction; Injury; Institution; Ischemia; Knock-out; Lead; Link; MAPK3 gene; Measures; Mediating; Membrane Potentials; Mentors; Mitochondria; Modeling; Molecular; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Nuclear Envelope; Nuclear Receptors; Outcome; Oxygen Consumption; Pathway interactions; Permeability; Pharmacological Treatment; Physiological; Predisposition; Prevalence; Proteins; Protons; Receptor Inhibition; Receptor Signaling; Recovery; Recurrence; Regulation; Reperfusion Injury; Reperfusion Therapy; Repression; Research; Risk; Risk Factors; SLC25A4 gene; Sampling; Serotonin; Serotonin Receptor 5-HT2B; Signal Pathway; Signal Transduction; Small Interfering RNA; Stains; Stimulus; Stress; System; Testing; Therapeutic Intervention; Training; Transcriptional Regulation; Western Blotting; Woman; Writing; antagonist; biological adaptation to stress; cardioprotection; career; career development; chromatin immunoprecipitation; depressed patient; heart function; high risk; human female; improved; in vivo; men; mitochondrial dysfunction; mitochondrial membrane; mortality; mortality risk; myocardial injury; promoter; protective effect; response; serotonin 5 receptor; serotonin receptor; sex; sexual dimorphism; skills

Project Summary/Abstract The prevalence of heart attacks has increased among women between 35-50 years of age compared to men of the same age. In contrast to men, women have a higher risk of mortality and complications after a heart attack due to the under-representation of women in clinical trials, the lack of gender-tailored pharmacological treatments, and potential higher vulnerability of women than for men to traditional and emerging risk factors. Stress has emerged as an important risk factor for heart disease in women; stress levels have been shown to correlate with delayed recovery, recurrence, and increased mortality after a heart attack in women. Sex hormones are considered the critical regulators of the physiological differences between men and women in health and disease. These hormones certainly contribute to sexual dimorphism in heart disease; however, the effects of gender on the incidence and outcomes of a heart attack are more complex and are unlikely to be due to sex hormones alone. The goal of the present proposal is to define one of the signaling pathways underlying the deleterious effects of stress on female cardiac health in the setting of myocardial ischemia (heart attack). To accomplish this goal, we propose to investigate the mechanisms whereby glucocorticoids (the primary stress hormones) affects estrogen cardioprotection in myocardial ischemia by repressing serotonin activity in cardiomyocytes via glucocorticoid inhibition of estrogen transcriptional regulation of the serotonin receptor 5- HT2BR (implicated in cardioprotection through the regulation of mitochondrial function in cardiomyocytes). A decrease in serotonin activity has been associated with increased risk of myocardial infarction in depressed patients, and also polymorphisms in serotonin receptors are associated with elevated glucocorticoid response linked to cardiovascular complications, including an increased incidence of heart attacks. Therefore, we aim to elucidate estrogen regulatory mechanism of 5-HT2BR expression in the heart and the effects of glucocorticoids on estrogen-mediated 5-HT2BR signaling in ischemia/reperfusion (I/R). We hypothesize that stress exerts deleterious effects on the female heart in myocardial infarction by exacerbating mitochondrial dysfunction via glucocorticoids inhibition of estrogen transcriptional regulation of 5-HT2BR in cardiomyocytes. We will investigate this pathway by examining glucocorticoid and estrogen antagonism in cardiomyocytes, the effects of this crosstalk in I/R (in vivo studies), and the molecular and physiological effects of 5-HT2BR regulation by estrogen in mitochondrial function in ischemic conditions. If funded, this application will help me develop a scientifically independent project, acquire training in the cardiovascular field, build a research team, enhance my mentoring skills, and improve my grant writing skills to become competitive to apply to a major funding mechanism. My current institution and my mentor and co-mentor will provide me with the necessary facilities and guidance to accomplish these goals. Also, I will participate in training and career development activities that will strengthen my scientific career.

项目总结/摘要 35 - 50岁的妇女心脏病发作的发病率比35 - 50岁的男子有所增加。 同样的年龄。与男性相比，女性心脏病发作后死亡率和并发症的风险更高 由于女性在临床试验中的代表性不足，缺乏针对性别的药理学 妇女比男子更容易受到传统和新出现的风险因素的影响。 压力已成为女性心脏病的重要危险因素;压力水平已被证明 与女性心脏病发作后延迟恢复、复发和死亡率增加相关。性 激素被认为是男女生理差异的关键调节剂， 健康和疾病。这些激素肯定有助于心脏病的两性异形;然而， 性别对心脏病发作的发生率和结局的影响更为复杂， 性激素的作用本提案的目标是确定一个信号通路的基础 在心肌缺血（心脏病发作）的情况下，压力对女性心脏健康的有害影响。到 为了实现这一目标，我们建议研究糖皮质激素（主要压力） 激素）通过抑制血清素活性影响雌激素在心肌缺血中的心脏保护作用。 通过糖皮质激素抑制雌激素对5-羟色胺受体的转录调节， HT2BR（通过调节心肌细胞中的线粒体功能参与心脏保护）。一 5-羟色胺活性的降低与抑郁症患者心肌梗死的风险增加有关。 5-羟色胺受体的多态性与糖皮质激素反应升高相关 与心血管并发症有关，包括心脏病发作的发病率增加。因此，我们的目标是 阐明雌激素对心脏5-HT2BR表达的调节机制及糖皮质激素的影响 在缺血/再灌注（I/R）中雌激素介导的5-HT2BR信号传导。我们假设压力 心肌梗死通过加重线粒体功能障碍对女性心脏的有害影响 糖皮质激素抑制雌激素对心肌细胞中5-HT2BR的转录调节。我们将调查 通过检测心肌细胞中糖皮质激素和雌激素的拮抗作用， I/R中的串扰（体内研究），以及雌激素对5-HT2BR调节的分子和生理作用 线粒体功能的变化。如果得到资助，这个应用程序将帮助我开发一个科学的 独立项目，获得心血管领域的培训，建立研究团队，加强我的指导 技能，并提高我的赠款写作技巧，成为有竞争力的申请到一个主要的资助机制。我 目前的机构和我的导师和共同导师将为我提供必要的设施和指导， 实现这些目标。此外，我将参加培训和职业发展活动， 我的科学生涯