Estrogen Receptor and Cardiovascular Function

描述(由申请人提供)： 最近对妇女健康倡议结果的重新评估表明，绝经后10年内补充雌激素可将心肌梗死的发生率降低34%。如果妇女在绝经后10年以上开始接受激素替代治疗，这种情况就不会发生。在细胞和小鼠模型中，雌激素降低了心肌肥厚的发生率，并从缺血/再灌注损伤中拯救心脏。到目前为止，在我们的研究中，雌激素(E2)通过ERSS起作用，在血管紧张素II(AngII)输注的情况下，作为人类疾病的模型，可以降低血压，防止心肌肥大和纤维化，并保护心脏功能。我们认为，E2/ERss阻断Ang II或ET-1(ET-1)诱导的心脏成纤维细胞向肌成纤维细胞的转化，并阻断TGFss的激活、结缔组织生长因子(CTGF)和基质金属蛋白酶的产生。这是由雌激素通过AMP激酶发出信号，阻止Rho/ROCK激活而发生的。最终结果是胶原基因转录减少，以及其他导致纤维化的基因，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，我们提出了E2/ERss上调apelin/APJ受体系统以阻止心肌细胞肥大的想法，并将在心肌细胞和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，而E2/ER�(和ER�特异性配体B-LGND)则阻止这一切，作为雌激素作用的新机制。在一定程度上，这是通过E2诱导HDAC5的核定位来实现的，HDAC5去乙酰化，从而维持KLF15对肌钙蛋白的抑制作用，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基因敲除的雌性和雄性小鼠，在高血压、心肌肥厚和纤维化的小鼠模型中测试GTx Inc.的一种新型ERss激动剂。假设这种配体将有效地预防和治疗血管紧张素转换酶诱导的WT小鼠心血管疾病，无论男女。这些数据可能会在未来对包括退伍军人在内的绝经后女性进行初步翻译试验。

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.