Estrogen Receptor and Cardiovascular Function

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年内的雌激素替代治疗使心肌梗死的发病率降低了34%。如果妇女在绝经后10年以上开始接受HRT，则不会发生这种情况。其他人和我们在细胞和小鼠模型中发现雌激素降低了心脏肥大的发生率，并从缺血/再灌注损伤中拯救了心脏。在我们迄今为止的研究中，雌激素（E2）通过ER β发挥作用，以降低血压，防止心脏肥大和纤维化，并在血管紧张素II（AngII）输注的情况下保护心脏功能，作为人类疾病的模型。我们认为E2/ER β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TGF β激活、结缔组织生长因子（CTGF）和基质金属蛋白酶的产生。这是通过AMP激酶的雌激素信号传导发生的，阻断Rho/ROCK激活。最终的结果是减少胶原蛋白基因转录，以及其他基因，有助于纤维化，所有将在分离的心脏成纤维细胞和小鼠模型中进行测试。作为第二个重点，我们提出了E2/ERss上调apelin/APJ受体系统以阻断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，以确定这种相互作用的重要性。抑制肥大基因的重要转录因子是KLF 15。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）阻止了这一切，这是雌激素作用的一种新机制。这部分地通过E2诱导的HDAC 5的核定位发生，HDAC 5去乙酰化并因此维持KLF 15对心肌蛋白的抑制作用，防止心肌细胞肥大。在最后的目标，我们建议测试一种新的ER β激动剂GTx公司在高血压，心脏肥大和纤维化的小鼠模型，使用野生型和ER β基因敲除的雌性和雄性小鼠。假设该配体将有效预防和治疗WT小鼠和两种性别中AngII诱导的心血管疾病。这些数据可能证明在未来的初步翻译试验绝经后妇女，包括退伍军人。

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.