Estrogen Receptor and Cardiovascular Function

雌激素受体与心血管功能

• 批准号: 8259069
• 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: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8259069
• 关键词: Agonist; Angiotensin II; Blood Vessels; Breast; Cardiac; Cardiac Myocytes; Cardiomegaly; Cardiovascular Models; Cardiovascular Physiology; Cell Nucleus; Cell membrane; Cell model; Cell physiology; Clinical Trials; Collagen; Collagen Gene; Cytoplasm; Data; Deposition; Deterioration; Development; Disease; Dropout; Endothelin-1; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Estrogen Replacements; Estrogens; Evaluation; Exclusion; Family; Female; Fibroblasts; Fibrosis; Future; Gene Expression; Genes; Genetic Transcription; Growth Factor; Heart; Heart Block; Heart Diseases; Heart Hypertrophy; Heart failure; Histones; Hormones; Human; Hypertension; Hypertrophy; In Vitro; Incidence; Knock-out; Lead; Mammary gland; Mediating; Menopause; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myofibroblast; Nuclear; Pharmaceutical Preparations; Pharmacologic Substance; Phosphorylation; Phosphotransferases; Postmenopause; Premenopause; Production; Progesterone; Receptor Signaling; Reperfusion Injury; Research; Rodent; Rodent Model; Role; Signal Transduction; Testing; Transforming Growth Factor beta; Uterine Cancer; Ventricular Function; Veterans; Woman; Women' s Health; abstracting; aged; heart function; human disease; human female; in vivo; male; malignant breast neoplasm; men; mouse model; novel; prevent; receptor function; 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. 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.

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。类似地，其他人和我们在细胞和小鼠模型中表明雌激素降低心脏肥大的发生率，并从缺血/再灌注损伤中拯救心脏。雌激素（E2）通过ER β发挥作用，以减少心脏肥大和保护心脏功能。一个重要的方面是E2/ER β阻断心脏纤维化，心脏纤维化主要由肥大因子如血管紧张素II（Ang II）引起。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活化和通过SMADs 2/3的信号传导。这导致胶原蛋白基因转录减少，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。作为第二个焦点，我们提出了E2/ER β上调II类HDAC产生并阻止这些抗肥大HDAC转运到细胞质（在那里它们不能抑制肥大）的想法。我们推测Ang II和ET-1刺激Ca++/CAM激酶诱导的II类HDAC磷酸化，导致核排斥，并被E2/ER β阻断。反过来，I类HDAC刺激心脏肥大，可能是通过引起GSK 3 β失活。我们认为E2/ER β抑制由Ang II或ET-1增强的I类HDAC合成，并阻断GSK 3 β的失活磷酸化，从而抑制心脏肥大。啮齿动物心肌细胞和小鼠模型都将用于测试这些目标。最后，我们建议使用野生型和ER β基因敲除的雌性和雄性小鼠，在肥大的小鼠模型中测试惠氏制药公司的一种新型ER β激动剂。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。 公共卫生相关性： 在25,000名绝经后妇女中进行的妇女健康倡议临床试验的结果表明，在绝经后10年内开始使用激素的妇女中，雌激素替代绝经明显减少了心脏病发作的发生。类似地，其他人和我们表明，雌激素减少了啮齿动物的心脏扩大，这通常是由于啮齿动物模型和人类控制不良的高血压造成的。我们认为雌激素阻止心脏扩大，损害心脏的正常功能，并可能导致心力衰竭。我们认为，雌激素通过雌激素受体之一发挥作用，可能会防止这种倾向于发展心脏扩大的妇女。通过给予一种非常有选择性的药物，刺激心脏中的雌激素受体，但不刺激乳腺癌或子宫癌，绝经后妇女（包括退伍军人）可能会受益。