CARDIAC ESTROGEN RECEPTORS AND MI-- MOUSE MODELS

心脏雌激素受体和 MI-- 小鼠模型

• 批准号: 6858699
• 负责人: RICHARD H KARAS
• 金额: $ 26.8万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6858699
• 关键词: arrhythmia; disease /disorder model; electrophysiology; estrogen inhibitor; estrogen receptors; estrogens; gender difference; gene expression; gene targeting; genetically modified animals; heart function; heart ventricle; hemodynamics; hormone regulation /control mechanism; immunocytochemistry; in situ hybridization; laboratory mouse; model design /development; morphometry; myocardial infarction; myocardial ischemia /hypoxia; myocardium; polymerase chain reaction; postmenopause; raloxifene; receptor expression

Ischemic cardiovascular disease, specifically myocardial infarction (MI), is the leading cause of morbidity and mortality in Western society. There are clear gender-based differences in cardiac function and electrophysiology that influence the two major sequelae following MI: heart failure (NF), and susceptibility to arrhythmias. In women, MI is uncommon prior to menopause and postmenopausal estrogen replacement therapy decreases its incidence. These beneficial effects of estrogen have been attributed previously to indirect effects on classic risk factors. However, estrogen is now recognized to have direct effects on cardiovascular cells that are central to its beneficial effects on cardiovascular disease. Estrogen's effects are mediated by receptors that act as ligand-activated transcription factors. Two such receptors are currently known, ERALPHA, and the recently discovered ERbeta. We have developed and reported a series of novel murine models that provide unique tools for pursuing mechanistic questions related to the pathophysiology of cardiovascular diseases. These include a mouse model of MI and a mouse cardiac electrophysiology (EP) model. We now present preliminary data from murine models demonstrating: (a) gender- based differences in cardiac electrophysiology, susceptibility to ventricular arrhythmias, and post-MI cardiac remodeling; (b) alteration in cardiac performance and electrophysiology in ERalpha (ERalphaKO) and ERbeta (ERbetaKO) knockout mice; (c) expression of both ERalpha and ERbeta and (d) ER-dependent effects on gene expression in cardiomyocytes. Taken together, these data identify the heart as a novel target organ for the direct effects of estrogen and form the basis for this Project's central hypothesis: Estrogen receptors regulate left ventricular remodeling and susceptibility to arrhythmias following myocardial infarction. We propose to test this hypothesis by pursuing two specific aims: Specific Aim 1: Investigation of the role of estrogen receptors an the effect of estrogen receptor modulators, including the SERM raloxifene, on left ventricular remodeling following myocardial infarction, using wild-type, ERalphaKO and ERbetaKO mice, and Specific Aim 2: Investigation of the role of estrogen receptors and the effect of estrogen receptor modulators on arrhythmias following myocardial infarction, using wild-type, ERalphaKO and ERbetaKO mice. These in vivo studies explore the molecular pathways that mediate gender-based and hormonal influences on cardiac remodeling and arrhythmias following MI. In addition, they provide a conceptual bridge from the genetic and clinical studies (Projects 1 and 2) to the other basic science projects (Projects 4 and 4) of this SCOR in ischemic heart disease.

缺血性心血管疾病，特别是心肌梗塞（MI），是西方社会发病率和死亡率的主要原因。心脏功能和电生理学有明显的基于性别的差异，这些差异会影响MI：心力衰竭（NF）和心律不齐的敏感性后的两个主要后遗症。在女性中，MI在更年期之前并不常见，绝经后雌激素替代疗法降低了其发病率。雌激素的这些有益作用先前归因于对经典危险因素的间接影响。然而，现在被认为对心血管细胞的有益作用对心血管疾病的有益作用至关重要。雌激素的作用是由充当配体激活转录因子的受体介导的。目前已知两个这样的受体Eralpha和最近发现的Erbeta。我们已经开发并报告了一系列新型的鼠模型，这些模型提供了独特的工具来追求与心血管疾病的病理生理学有关的机械问题。这些包括MI的小鼠模型和小鼠心脏电生理学（EP）模型。现在，我们提供了来自鼠模型的初步数据，证明了：（a）基于性别的心脏生理学，对心室心律不齐的敏感性和MI后心脏重塑的敏感性； （b）Eralpha（Eralphako）和Erbeta（Erbetako）敲除小鼠的心脏性能和电生理学的改变； （c）Eralpha和Erbeta的表达以及（D）ER依赖性对心肌细胞基因表达的影响。综上所述，这些数据将心脏确定为雌激素直接作用的新型靶器官，并构成了该项目的中心假设的基础：雌激素受体调节心肌梗塞后心律不齐的左心室重塑和易感性。 We propose to test this hypothesis by pursuing two specific aims: Specific Aim 1: Investigation of the role of estrogen receptors an the effect of estrogen receptor modulators, including the SERM raloxifene, on left ventricular remodeling following myocardial infarction, using wild-type, ERalphaKO and ERbetaKO mice, and Specific Aim 2: Investigation of the role of estrogen receptors and the effect of estrogen使用野生型，Eralphako和Erbetako小鼠，心肌梗塞后心律不齐的受体调节剂。这些体内研究探讨了MI后介导基于性别的基于性别的和激素对心脏重塑和心律不齐的影响的分子途径。此外，它们还提供了从遗传和临床研究（项目1和2）到该SCOR的其他基础科学项目（项目4和4）的概念桥梁。