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。同样，其他人和我们在细胞和小鼠模型中表明雌激素减少心肌肥厚的发生率，并从缺血/再灌注损伤中拯救心脏。雌激素(E_2)通过内质网起作用，减轻心肌肥厚，保护心脏功能。一个重要的方面是，E2/ERss可以阻止由血管紧张素II(Ang II)等肥大因子引起的心肌纤维化。我们认为，E2/ERss阻断Ang II或ET-1诱导的心脏成纤维细胞向肌成纤维细胞的转化，并通过Smads 2/3阻断TGFss的激活和信号转导。这导致胶原基因转录减少，以及其他导致纤维化的基因。这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，我们提出了这样的想法，即E2/ERss上调II类HDAC的产生，并阻止这些抗肥大的HDAC运输到细胞质(在那里它们无法抑制肥大)。我们推测，Ang II和ET-1刺激Ca++/CAM激酶诱导的II类HDAC的磷酸化，导致核排斥，并被E2/ERss阻断。反过来，I类HDAC可能通过使GSK3ss失活来刺激心肌肥厚。我们认为，E2/ERss抑制Ang II或ET-1促进的I类HDAC合成，并阻断GSK3ss的失活磷酸化，从而抑制心肌肥厚。将使用啮齿动物心肌细胞和小鼠模型来测试这些目标。最后，我们建议使用野生型和ERss基因敲除的雌性和雄性小鼠，在肥大小鼠模型中测试来自惠氏制药公司的一种新型ERss激动剂。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。 公共卫生相关性： 《妇女健康倡议》对2.5万名绝经后妇女进行的临床试验结果表明，在绝经后10年内开始使用激素的妇女中，绝经后服用雌激素替代疗法明显减少了心脏病发作的发生。同样，其他人和我们表明，雌激素可以减少啮齿动物的心脏增大，这种增大通常是由于啮齿动物模型和人类的高血压控制不佳造成的。我们建议雌激素阻止心脏增大，心脏增大会损害心脏的正常功能，并可能导致心力衰竭。我们认为，雌激素通过一种雌激素受体发挥作用，可能会阻止有心脏增大倾向的女性发生这种情况。通过给予一种非常有选择性的药物来刺激心脏中的雌激素受体，但不会刺激乳腺癌或子宫癌，绝经后的女性(包括退伍军人)可能会受益。

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. Similarly, 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. Estrogen (E2) acts through ERss to reduce cardiac hypertrophy and preserve cardiac function. An important aspect is that E2/ERss block cardiac fibrosis that is prominently caused by hypertrophic factors such as Angiotensin II (Ang II). We propose that E2/ERss block Ang II or endothelin-1 (ET-1) induced transition of the cardiac fibroblast to myofibroblast and blocks TGFss activation and signaling through SMADs 2/3. This results in decreased collagen gene transcription, as well as other genes that contribute to fibrosis. This will be tested in isolated cardiac fibroblast and mouse models. As a second focus, we propose the idea that E2/ERss up-regulates class II HDAC production and prevents transport of these anti-hypertrophic HDACs to the cytoplasm (where they cannot repress hypertrophy). We hypothesize that Ang II and ET-1 stimulate Ca++/CAM kinase-induced phosphorylation of class II HDACs that results in nuclear exclusion, blocked by E2/ERss. Reciprocally, class I HDACs stimulate cardiac hypertrophy, perhaps by causing the inactivation of GSK3ss. We propose that E2/ERss inhibits class I HDAC synthesis that is augmented by Ang II or ET-1 and also blocks the inactivating phosphorylation of GSK3ss, thus inhibiting cardiac hypertrophy. Both rodent cardiomyocyte and mouse models will be used to test these aims. Finally, we propose to test a novel ERss agonist from Wyeth Pharmaceutical in a mouse model of hypertrophy, using wild type and ERss knockout female and male mice. These data may justify in the future initial translational trials in post-menopausal women, including veterans. PUBLIC HEALTH RELEVANCE: Narrative The results of the Women's Health Initiative clinical trial in 25,000 post-menopausal women shows that in women starting hormones within 10 years of the menopause, estrogen replacement menopause clearly reduced the occurrence of heart attacks. Similarly, others and we showed that estrogen reduces heart enlargement in rodents that typically results from poorly controlled high blood pressure in rodent models and in humans. We propose that estrogen blocks heart enlargement that compromises the normal function of the heart and can lead to heart failure. We propose that estrogen acting through one of the estrogen receptors may prevent this in women who are disposed to developing heart enlargement. By giving a very selective drug that stimulates the estrogen receptor in the heart, but does not stimulate breast or uterine cancer, post-menopausal women (including veterans) may benefit.