Estrogen receptor and the cardiovascular system

雌激素受体与心血管系统

• 批准号: 9554539
• 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 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9554539
• 关键词: APLN gene; Acetylesterase; Acute; Agonist; Angiotensin II; Animal Model; Animals; Antihypertensive Agents; Atherosclerosis; Binding; Blood Pressure; Breast; Cardiac; Cardiac Myocytes; Cardiac development; Cardiomegaly; Cardiovascular Diseases; Cardiovascular system; Cell Nucleus; Cell membrane; Cell model; Cells; Clinical Trials; Complex; Cre-LoxP; Data; Development; Disease; Disease Progression; Dose; EP300 gene; Epigenetic Process; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Estrogen Replacements; Estrogens; Event; Female; Fibrosis; G-Protein-Coupled Receptors; Gene Proteins; Genes; Growth Factor; HDAC5 gene; Heart; Heart Block; Heart Diseases; Heart Hypertrophy; Heart Ventricle; Heart failure; Histologic; Histone Deacetylase; Hormone replacement therapy; Hormones; Human; Hypertension; Hypertrophy; In Vitro; Incidence; Infusion procedures; Knockout Mice; Left; Ligands; Mammals; Membrane; Menopause; Messenger RNA; Modeling; Mus; Muscle Cells; Myocardial Infarction; Neonatal; Nuclear; Nuclear Proteins; Peptides; Pharmaceutical Preparations; Placebos; Postmenopause; Prevention; Process; Property; Prospective Studies; Protein Isoforms; Proteins; Rattus; Reperfusion Injury; Rodent; Role; Signal Transduction; System; Testing; Uterine Cancer; Uterus; Ventricular; Veterans; Woman; Women' s Health; advanced disease; coronary fibrosis; estrogenic; functional disability; heart function; human disease; human female; human model; in vivo; in vivo Model; male; malignant breast neoplasm; men; mouse model; myocardin; prevent; protein expression; receptor; recruit; response; transcription factor

Project Summary/Abstract Estrogen action has been shown in animal models and to an extent in humans to mitigate various forms of cardiovascular disease, including hypertension, atherosclerosis, and ischemia/reperfusion injury. Estrogen acts at its receptors, ERalpha and ERbeta. There is also strong data that estrogen prevents the development of cardiac hypertrophy, fibrosis, and progression to heart failure, particularly in human-relevant animal models when started early in the course of disease. These effects of estrogen are mainly through actions at the ERbeta isoform, especially from the membrane-localized pool that stimulates signal transduction. One potential target of ERbeta is the important transcription factor, KLF15 that is proposed to have anti- hypertrophic properties. Using a relevant model for human disease, involving low dose Angiotensin II (Ang II) infusion over 4 weeks in ovariectomized, wild type and ERbeta KO female mice will occur. The impact of AngII and estradiol (E2) or an ERbeta-specific agonist, -LGND2, is used to determine effects on the expression of this transcription factor in the left cardiac ventricle, postulating that membrane E2/ERbeta signaling restores the expression of KLF15 that is reduced by AngII alone infusion. Male mice will also be investigated. Also, in- vitro studies using cultured, freshly isolated neonatal rat cardiomyocytes will determine whether AngII reduces, while E2 or BLGND restores nuclear localization of KLF15, and interaction with important hypertrophy- controlling nuclear proteins such as myocardin, SRF, GATA-2 and MEF, and recruit epigenetic regulators including HDACs 2 and 5, and p300. We propose this regulates important myocyte effector genes/protein expression and myocyte function that will be determined. Whether nuclear ERcontributes will be determined in 2 cell models of cell-selective ER pool loss. An important cardiovascular protein and its myocyte cell membrane receptor, apelin and APJ respectively, are known to mitigate the development of cardiac hypertrophy, fibrosis, and disease progression. It may be that membrane ERbeta signaling and actions require this complex and activation of this system at the abundance and functional levels. This will be determined in-vitro and in-vivo, the latter using ovariectomized, wild type, ERbeta KO, and cardiomyocyte-specific APJ KO mice (Cre-Flox). This model will definitively implicate the role of APJ in these cells for the action of E2/ERbeta to mitigate in-vivo AngII effects on blood pressure and cardiac hypertrophy, fibrosis, and cardiac functional compromise. Male mice will also be used. Two compelling issues in considering whether a proprietary ERbeta agonist could eventually be used in humans are whether ERbeta activation 1) reverses established disease, and 2) whether this might be relevant to male mammals. The 4 week model of AngII infusion +/- E2 or BLGND will be done in ovariectomized female WT and ERbeta KO mice, where AngII is started 2 weeks earlier than estrogenic compound administration, sufficient to induce cardiac changes. This tests whether this early disease state can be reversed by E2 or BLGND. Also, treatment and prevention studies of cardiac disease from AngII infusion will be carried out in male mice treated with E2 or BLGND including normalization of AngII-induced hypertension. Whether ER contributes to the anti-hypertensive effects of E2 will also be determined using ER KO mice.

项目总结/摘要 雌激素的作用已在动物模型中显示，并在一定程度上在人类中显示，以减轻各种形式的 心血管疾病，包括高血压、动脉粥样硬化和缺血/再灌注损伤。雌激素作用 受体ER α和ER β。也有强有力的数据表明，雌激素可以阻止 心脏肥大、纤维化和进展为心力衰竭，特别是在人类相关动物模型中 在疾病早期就开始了。雌激素的这些作用主要是通过作用于 ER β亚型，尤其是来自刺激信号转导的膜定位池。 ER β的一个潜在靶点是重要的转录因子KLF 15，它被认为具有抗ER β的作用。 肥大特性。使用涉及低剂量血管紧张素II（Ang II）的人类疾病相关模型 将在卵巢切除的野生型和ER β KO雌性小鼠中进行4周的输注。AngII的影响 和雌二醇（E2）或ER β-特异性激动剂，IL-LGND 2，用于确定对以下表达的影响： 这种转录因子在左心室，假设膜E2/ER β信号恢复 单独输注AngII可降低KLF 15的表达。还将研究雄性小鼠。此外，在- 使用培养的、新鲜分离的新生大鼠心肌细胞的体外研究将确定AngII是否减少， 而E2或BLGND恢复KLF 15的核定位，并与重要的肥大相互作用- 控制核蛋白如心肌蛋白、SRF、加塔-2和MEF，并募集表观遗传调节因子 包括HDAC 2和5以及p300。我们提出这调节重要的肌细胞效应基因/蛋白质 表达和肌细胞功能将被确定。核反应堆是否有贡献将取决于 在2个细胞选择性ER受体池丢失的细胞模型中。 一种重要的心血管蛋白及其肌细胞膜受体apelin和APJ分别是 已知可减轻心脏肥大、纤维化和疾病进展的发展。可能是 膜ER β信号传导和作用需要这种复合物，并激活这种系统， 功能水平。这将在体外和体内测定，后者使用卵巢切除的野生型， ERbeta KO和心肌细胞特异性的APJ KO小鼠（Cre-Flox）。这个模型将明确地暗示 E2/ER β减轻体内AngII对血压和心脏的影响 肥大、纤维化和心脏功能受损。还将使用雄性小鼠。 在考虑专利的ER β激动剂是否最终可以用于治疗 人类的问题是ER β激活是否1）逆转已建立的疾病，以及2）这是否可能与 雄性哺乳动物。AngII输注+/- E2或BLGND的4周模型将在卵巢切除的雌性动物中进行 WT和ER β KO小鼠，其中AngII比雌激素化合物给药早2周开始， 足以引起心脏变化。这测试了这种早期疾病状态是否可以通过E2或 BLGND。此外，还将开展AngII输注引起的心脏病的治疗和预防研究， 用E2或BLGND治疗的雄性小鼠，包括AngII诱导的高血压的正常化。是否ER 还将使用ER β KO小鼠确定E2的抗高血压作用的贡献。