Estrogen Receptor and Cardiovascular Function

雌激素受体与心血管功能

• 批准号: 8737481
• 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/8737481
• 关键词: Agonist; Angiotensin II; Blood Pressure; 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 Factor; HDAC5 gene; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Hormones; Human; Hypertension; Hypertrophy; In Vitro; Incidence; Infusion procedures; Knock-out; 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; Uterine Cancer; Ventricular Function; Veterans; Woman; Women' s Health; abstracting; adenylate kinase; aged; connective tissue growth factor; 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; public health relevance; 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）： 摘要对妇女健康倡议结果的重新评估表明，更年期后的10年内雌激素替代将心肌梗塞的事件降低了34％。绝经后十多年后，妇女在HRT上启动了妇女，就不会发生这种情况。其他人，我们表明雌激素减少了心脏肥大的入口，并反应细胞和小鼠模型中缺血/再灌注损伤的心脏。在我们迄今为止的研究中，E2/ERSS阻止了心脏成纤维细胞向肌纤维细胞向肌成纤维细胞的过渡，并阻止TGFSS激活，结缔组织生长因子（CTGF）和基质元蛋白酶产生。这是通过通过AMP激酶信号传导而发生的，从而阻断了Rho/Rock活化。 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 相互作用。反映肥厚基因的重要转录因子是KLF15。我们建议ANGII和ET-1抑制了这种抗嗜性因子的产生和核定位，但是E2/ER¿（以及Er¿特定的配体，B-LGND）阻止了所有这些，作为雌激素作用的新机制。在某种程度上，这是通过E2诱导的HDAC5核定位置发生的，HDAC5脱离乙酰酸盐，因此保持KLF15对肌心蛋白的反射作用，从而防止心肌细胞肥大。在最终目标中，我们建议使用野生型和ERSS基因敲除雌性和雄性小鼠在小鼠的高血压，心肥力和纤维化的小鼠模型中测试GTX Inc的新型ERSS激动剂。假设是，该配体将有效预防和治疗WT小鼠和两性中的Angii诱导的心血管疾病。这些数据可能会在未来的绝经后妇女（包括退伍军人）的初步转化试验中证明是合理的。