Nitric Oxide and sex differences in cardiac repair

一氧化氮和心脏修复中的性别差异

• 批准号: 9331951
• 负责人: Joshua M Hare
• 金额: $ 40.61万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-17 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9331951
• 关键词: Affect; Agonist; Alcohol dehydrogenase; Angiotensin II; Antioxidants; Attention; Buffers; Cardiac; Cardiac Myocytes; Cardiovascular Abnormalities; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cause of Death; Clinical; Complication; Cysteine; Data; Development; Disease Outcome; Enzymes; Equilibrium; Estrogen Receptors; Exhibits; Female; Gender; Glutathione Disulfide; Heart; Heart Diseases; Hormonal; Injury; Lead; Mediating; Menopause; Modeling; Mus; Myocardial Infarction; Myocardial dysfunction; Nitric Oxide; Outcome; Oxidation-Reduction; Oxidative Stress; Oxidoreductase; PPAR gamma; Pathology; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Phenotype; Phosphorylation; Physiological; Play; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Premenopause; Process; Production; Protein S; Proteins; Proteinuria; Reactive Oxygen Species; Regulation; Role; S-Nitrosoglutathione; Sex Characteristics; Signal Pathway; Signal Transduction; Signaling Protein; Site; Source; Stress; Sulfhydryl Compounds; Syndrome; System; TXN gene; Testing; Therapeutic; Treatment Efficacy; Vascular blood supply; Woman; ascorbate; base; calmodulin-dependent protein kinase II; cardiac repair; cardiovascular health; effective therapy; experience; gender difference; improved; insight; male; maternal hypertension; men; mortality; novel; oxidative damage; pregnant; programs; protective effect; response; sex; stressor

Project Summary: This program will have a major impact in the treatment of cardiovascular disease (CVD), the leading cause of death in men and women globally. Premenopausal women are less susceptible to heart disease than men, and this protection is lost after menopause. Emerging data suggest that the interplay between nitric oxide (NO) and reactive oxygen species (ROS), the nitroso-redox balance, plays a critical role in this sex-related cardioprotection. Elucidating the mechanisms underlying these gender differences is critical for development of effective therapies. S-nitrosylation (S-NO) of cysteine thiols is a major signaling pathway through which NO exerts its broad regulatory actions. It is increasingly appreciated that the underlying signaling fate of NO ultimately depends upon an intracellular state of nitroso-redox balance; such that excessive production of ROS can disrupt physiological S-NO and that CVD may reflect dysregulated protein S- NO. We have shown that the nitroso/redox balance is an important regulator of CV health and disease. Female mice have 65% more S-nitrosylated proteins in the heart6 and physiologically regulate this elevated level of S- NO with increased activity of S-nitrosoglutathione (GSNO) reductase (GSNOR), an enzyme that promotes protein denitrosylation. We previously showed that male mice lacking S-nitrosoglutathione (GSNO) reductase, an enzyme that governs S-NO levels by promoting protein denitrosylation (GSNOR−⁄− mice) exhibit improved survival after myocardial infarction (MI). Furthermore, pregnant GSNOR−/− mice exhibit all of the clinical features of a major complication in pregnancy, preeclampsia (PE), including maternal hypertension, proteinuria and abnormal CV adaptation. Poor outcome in the GSNOR−/− females may be due to oxidative stress, as our preliminary data shows that cardiomyocytes (CMs) from GSNOR−/− females generate more ROS as compared to CMs from control females and GSNOR−/− males. Therefore, the state of increased S-NO can lead to an adverse milieu if accompanied by oxidative stress and we have uncovered a sex-associated relationship between cardiac pathology and intra-cellular nitroso-redox imbalance, which is dependent on NO and ROS production and S-NO formation and denitrosylation. Our central hypothesis is that the absence of GSNOR produces a sex-specific, antioxidant milieu in the setting of normal ROS levels (i.e., males) but one of nitrosative/oxidative stress when ROS is elevated (i.e., females). Our proposal aims to identify the fundamental mechanisms underlying this dichotomy. The specific aims are to test the hypotheses that 1) differences in nitroso-redox protein signaling determine sex-specific responses to CV stress; 2) nitroso-redox imbalance in cadiomyocytes during pregnancy underlies pregnancy-related CVD; and 3) GSNOR produces sex-specific changes in the S-nitrosylation of proteins that alter CV function. Together these aims will provide novel insights into nitroso-redox regulation of cardiac function in response to physiologic and pathophysiologic stressors and have significant implications for the treatment of CVD in men and women.

项目摘要：该计划将对心血管疾病（CVD）的治疗产生重大影响， 全球男女死亡的主要原因。绝经前妇女不太容易受到心脏的影响 疾病比男性疾病，更年期后这种保护却丢失了。新兴数据表明相互作用 一氧化氮（NO）和活性氧（ROS）（硝基氧平衡）在 这种与性别相关的心脏保护作用。阐明这些性别差异的基础机制对于 开发有效的疗法。半胱氨酸硫醇的S-亚硝基化（S-NO）是主要信号通路 通过它没有出口其广泛的监管行为。越来越多地赞赏基础 NO的信号命运最终取决于氮 - 雷多斯平衡的细胞内状态。这样 ROS的过度产生会破坏生理S-NO，而CVD可能反映了失调的蛋白质S- 不。我们已经表明，硝基/氧化还原平衡是简历健康和疾病的重要调节剂。女性 小鼠在HERT6中具有65％的S-亚硝基化蛋白，并在物理上调节S-的水平升高 NO的活性增加了S-硝基谷硫硫代（GSNO）还原（GSNOR），这是一种促进的酶 蛋白质硝化基化。我们以前表明缺乏S-硝基谷硫硫代（GSNO）还原酶的雄性小鼠， 通过促进蛋白质脱硝化（GSNOR-⁄-小鼠）来改善的蛋白质脱硝化（GSNOR-⁄-小鼠）来控制S-NO水平的酶 心肌梗塞后的生存（MI）。此外，孕妇的gsnor - / - 小鼠暴露了所有临床 怀孕，先兆子痫（PE）的主要并发症的特征，包括母体高血压，蛋白尿 和简历适应异常。 GSNOR - / - 女性的结果不佳可能是由于氧化应激所致，因为我们 初步数据表明，GSNOR - / - 女性的心肌细胞（CMS）会产生更多的ROS 从控制女性和GSNOR - / - 雄性到CM。因此，s-no的状态可能导致 不利环境如果通过氧化应力管理，我们已经发现了与性别相关的关系 心脏病理学和细胞内氮 - 雷多斯不平衡之间，这取决于NO和ROS 生产和S-NO的形成和硝基化。我们的中心假设是缺乏GSNOR 在正常的ROS水平（即男性）的环境中产生一个性别特异性的抗氧化环境 ROS升高时（即女性）时的硝化/氧化应激。我们的建议旨在确定基本 该二分法的基础机制。具体目的是测试假设1） 硝基 - 雷克斯蛋白信号传导确定对CV应激的性别特异性反应； 2）Nitroso-Redox不平衡 怀孕期间的卡admy菌细胞是与怀孕相关的CVD的基础； 3）GSNOR会产生特定的性别 改变CV功能的蛋白质的S-亚硝基化变化。这些目标共同提供新颖的见解 响应生理和病理生理胁迫响应心脏功能的硝基 - 雷多斯调节 对男性和女性的CVD治疗具有重要意义。