Estrogen Receptor and Cardiovascular Function

雌激素受体与心血管功能

• 批准号: 8974357
• 负责人: ELLIS R LEVIN
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8974357
• 关键词: Agonist; Angiotensin II; Blood Vessels; Breast; Cardiac; Cardiac Myocytes; Cardiomegaly; Cardiovascular Diseases; Cardiovascular Models; Cardiovascular Physiology; Cell membrane; Cell model; Cell physiology; Clinical Trials; Collagen Gene; Cyclic AMP-Dependent Protein Kinases; Data; Development; Disease; Endothelin-1; Epidermal Growth Factor Receptor; Estradiol; Estrogen Receptor beta; Estrogen Receptors; Estrogen Replacements; Estrogens; Evaluation; Female; Fibroblasts; Fibrosis; Future; Genes; Genetic Transcription; Growth; HDAC5 gene; Health; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Hormones; Human; Hypertension; Hypertrophy; In Vitro; Incidence; Infusion procedures; Knock-out; Knockout Mice; Ligands; Mammary gland; Menopause; Modeling; Mus; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myofibroblast; Nuclear; Peptide Hydrolases; Pharmaceutical Preparations; Phosphotransferases; Postmenopause; Premenopause; Process; Production; Progesterone; Proteins; Publishing; Receptor Activation; Receptor Signaling; Reperfusion Injury; Reporting; Rho-associated kinase; Rodent; Role; Signal Transduction; System; Testing; Translational trial; Uterine Cancer; Ventricular Function; Veterans; Woman; Women' s Health; abstracting; adenylate kinase; aged; blood pressure reduction; connective tissue growth factor; coronary fibrosis; efficacy testing; heart function; human disease; human female; in vivo; inhibitor/antagonist; male; malignant breast neoplasm; men; mouse model; myocardin; novel; older women; pre-clinical; prevent; receptor; receptor function; response; rho; sex; transcription factor

DESCRIPTION (provided by applicant): Abstract Recent re-evaluation of the results of the Women's Health Initiative shows that estrogen replacement within 10 years of the menopause reduced the incidence of myocardial infarction by 34%. This did not occur if women were started on HRT more than 10 years after the menopause. Others and we showed that estrogen reduces the incidence of cardiac hypertrophy and rescues the heart from ischemia/reperfusion injury in cell and mouse models. In our studies to date, estrogen (E2) acts through ERss to reduce blood pressure, prevent cardiac hypertrophy and fibrosis, and preserve cardiac function in the setting of angiotensin II (AngII) infusion, as a model for human disease. We propose that E2/ERss blocks Ang II or endothelin-1 (ET-1) induced transition of the cardiac fibroblast to myofibroblast and blocks TGFss activation, connective tissue growth factor (CTGF), and matrix mettalloproteinase production. This occurs by estrogen signaling through AMP kinase, blocking Rho/ROCK activation. The ultimate result is decreased collagen gene transcription, as well as other genes that contribute to fibrosis, and all will be tested in isolated cardiac fibroblast and mouse models As a second focus, we propose the idea that E2/ERss up-regulates the apelin/APJ receptor system to block cardiomyocyte hypertrophy, and we will test this concept in myocytes and the apelin KO mouse to establish importance of this interaction. An important transcription factor that represses hypertrophic genes is KLF15. We propose that AngII and ET-1 inhibit the production and nuclear localization of this anti-hypertrophic factor, but E2/ER� (and the ER� specific ligand, B-LGND) prevent all this, as a novel mechanism for estrogen action. In part this occurs through E2-induced nuclear localization of HDAC5 that de-acetylates and hence maintains the repressive effect of KLF15 on myocardin, preventing cardiomyocyte hypertrophy. In the final Aim, we propose to test a novel ERss agonist from GTx Inc in a mouse model of hypertension, cardiac hypertrophy and fibrosis, using wild type and ERss knockout female and male mice. The hypothesis is that this ligand will be effective in preventing and treating AngII-induced cardiovascular diseases in WT mice, and in both sexes. These data may justify in the future initial translational trials in post-menopausal women, including veterans.

描述（由申请人提供）： 摘要 最近对妇女健康倡议结果的重新评估表明，绝经后 10 年内补充雌激素可使心肌梗塞的发生率降低 34%。如果女性在绝经后 10 多年才开始接受 HRT，则不会发生这种情况。其他人和我们都表明，雌激素可以降低细胞和小鼠模型中心脏肥大的发生率并挽救心脏免受缺血/再灌注损伤。在我们迄今为止的研究中，雌激素 (E2) 通过 ERss 发挥作用，降低血压，预防心脏肥大和纤维化，并在血管紧张素 II (AngII) 输注的情况下保持心脏功能，作为人类疾病的模型。我们认为 E2/ERss 阻断 Ang II 或内皮素-1 (ET-1) 诱导的心脏成纤维细胞向肌成纤维细胞的转变，并阻断 TGFs 激活、结缔组织生长因子 (CTGF) 和基质金属蛋白酶的产生。这是由雌激素信号通过 AMP 激酶阻断 Rho/ROCK 激活而发生的。最终结果是胶原蛋白基因转录减少，以及导致纤维化的其他基因减少，所有这些都将在分离的心脏成纤维细胞和小鼠模型中进行测试。作为第二个焦点，我们提出 E2/ERss 上调 apelin/APJ 受体系统以阻止心肌细胞肥大的想法，我们将在肌细胞和 apelin KO 小鼠中测试这一概念，以确定这一概念的重要性 相互作用。抑制肥大基因的一个重要转录因子是 KLF15。我们认为 AngII 和 ET-1 抑制这种抗肥大因子的产生和核定位，但 E2/ER�（和 ER� 特异性配体 B-LGND）作为雌激素作用的一种新机制，阻止了这一切。在某种程度上，这是通过 E2 诱导 HDAC5 的核定位发生的，HDAC5 去乙酰化，从而维持 KLF15 对心肌素的抑制作用，防止心肌细胞肥大。在最终目标中，我们建议使用野生型和 ERss 敲除雌性和雄性小鼠，在高血压、心脏肥大和纤维化的小鼠模型中测试 GTx Inc 的新型 ERss 激动剂。假设该配体将有效预防和治疗 WT 小鼠和两性小鼠中 AngII 诱导的心血管疾病。这些数据可能证明未来对绝经后妇女（包括退伍军人）进行的初步转化试验是合理的。