Cardiomyocyte Apoptosis and Cardioprotective Actions of Estrogen

心肌细胞凋亡与雌激素的心脏保护作用

• 批准号: 8437485
• 负责人: Jin Kyung Kim
• 金额: $ 38.45万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8437485
• 关键词: Age; Animal Model; Apoptosis; Apoptotic; Biological; Biological Preservation; Biology; Cardiac; Cardiac Myocytes; Cell Culture System; Cell Death; Cell Fate Control; Cell Survival; Cell physiology; Cells; Cellular Structures; Coronary artery; Cytoprotection; Data; Echocardiography; Estradiol; Estrogen Receptors; Estrogens; Feedback; Female; Gender; Goals; Heart; Heart failure; Hormones; In Situ; In Vitro; Injury; Investigation; Ischemia; Knowledge; Ligation; MAPK14 gene; Mediating; Mediator of activation protein; Mitochondria; Mitogen-Activated Protein Kinases; Myocardial Infarction; Myocardial Ischemia; Nature; Null Lymphocytes; Organ; Oxidative Stress; Pathway interactions; Phosphotransferases; Play; Post-Translational Protein Processing; Premenopause; Protein Isoforms; Proteins; Rattus; Receptor Signaling; Regulation; Reperfusion Injury; Role; Sex Characteristics; Signal Transduction; Simulate; Stress; Testing; Therapeutic; Translating; Ursidae Family; Woman; cell type; human MAPK14 protein; in vivo Model; insight; men; mitogen-activated protein kinase p38; mortality; novel; public health relevance; therapy development

DESCRIPTION (provided by applicant): Ischemic heart disease (IHD) is the leading cause of mortality in this nation. Studies have shown that more premenopausal women are protected from IHD than age-matched men. However, the mechanisms underlying the gender difference are not clear. Scientific data show that the endogenous female hormone, 17-betaestradiol (E2) may be responsible for protecting heart muscle cells (cardiomyocytes). Our goal is to determine how E2 protects cardiomyocytes under ischemic stress. We hypothesize that estrogen signals to several important regulators of cell fate in ischemic stress - cardiac p38 mitogen-activated protein kinases (p38 MAPKs) and p53, a well-known mediator of apoptosis - to protect the cardiomyocyte. We will investigate how E2 mediates the novel relationship between cardiac p38 MAPKs and p53 in mitochondria-driven cell death, the dominant pathway of cardiac apoptosis. In Specific Aim 1, we will establish the role of E2 in cardiac p38 MAPK regulation. The p38 MAPK subtypes, p38¿ and p38¿, possess distinct independent functions, with the former participating in apoptosis and the latter in preservation of cellular structure. We will subject cultured rat cardiomyocytes to simulated ischemia-reperfusion injury (I/R) and [A] examine the effect of E2 on each p38 isoform; [B] correlate the E2-specific effects on each kinase to mitochondria-centered apoptosis; and [C] identify the target(s) of p38¿ and p38¿ in the mitochondria. We will correlate data from cells to an in-vivo model of I/R in female ovariectomized rats with or without E2 supplement and examine p38¿, p38¿, cardiac apoptosis in situ, and cardiac function by echocardiography. In Specific Aim 2, we will investigate how E2 mediates p38 MAPKs - p53 interaction. p53 is a substrate of pro-apoptotic p38¿ in different cell types. We will [A] establish that p53 is phosphorylated by the p38¿ in cardiomyocytes; and [B] detail the nature of the posttranslational modification with respect to p38¿-mediated cell death. We will also [A] investigate if p38¿ phosphorylates p53, and if so, what biological significance such a relationship bears in I/R-triggered apoptosis; [B] explore a possibility of a feedback mechanism between p53 and p38¿; [C] determine how E2 modulates the dynamic between p53 and p38¿; and [D] translate and confirm findings in a whole animal model of I/R injury by detailing p53-specific changes in cardiac p38 expression and activation at the organ level. In Specific Aim 3, we will define the role of estrogen receptor (ER) subtypes in cardiomyocyte protection. We suspect that both ER subtypes (ER¿ and ER¿) are necessary for full cytoprotection from mitochondria-centered apoptosis. We will [A] delineate how each receptor signals to p38¿ and subsequent regulation of oxidative stress in mitochondria [B] identify and characterize endogenous ER ¿/¿ heterodimers in cardiomyocyte mitochondria, and [C] express a fusion ER ¿/¿ protein in ER-null cells and compare with ER homodimers in its ability to regulate apoptosis, mitochondrial p53 and p38 function.

描述（适用提供）：缺血性心脏病（IHD）是该国死亡率的主要原因。研究表明，与年龄匹配的男性相比，更多的绝经前女性受到IHD的保护。但是，性别差异的基础机制尚不清楚。科学数据表明，内源性雌马，17-β雌二醇（E2）可能负责保护心肌细胞（心肌细胞）。我们的目标是确定E2如何保护缺血性压力下的心肌细胞。我们假设雌激素信号向缺血性胁迫中的几个重要的细胞命运调节剂 - 心脏p38有丝分裂原激活的蛋白激酶（p38 mapks）和p53（p53）和p53是众所周知的凋亡介质 - 以保护心脏。我们将研究E2在线粒体驱动的细胞死亡中如何介导心脏p38 MAPK和p53之间的新型关系，这是心脏凋亡的主要途径。在特定目标1中，我们将确定E2在心脏p38 MAPK调节中的作用。 p38 MAPK亚型P38 p38 p38 ply具有独特的独立功能，前者参与了细胞凋亡，后者参与了细胞结构的保存。我们将对培养的大鼠心肌细胞进行模拟的缺血再灌注损伤（I/R），[a]检查E2对每个p38同工型的影响； [b]将每种激酶的E2特异性作用与以线粒体为中心的凋亡相关联； [c]在线粒体中识别p38 p38 p38 p38的靶标。我们将在女性卵巢卵巢切除大鼠中的数据与I/R的体内模型相关联，其中有或没有E2补充剂和检查p38 p38，p38 p，p38，心脏凋亡，而心脏功能以及超声心动图。在特定的目标2中，我们将研究E2如何介导P38 MAPK -P53相互作用。 p53是不同细胞类型的促凋亡p38 p38。我们将[a]确定p53在心肌细胞中被p38磷酸化。 [b]详细介绍了p38介导的细胞死亡的翻译后修饰的性质。我们还将[a]研究p38 p38是否磷酸化p53，如果是这样，这种关系在I/R触发的细胞凋亡中具有什么生物学意义； [b]探索p53和p38之间反馈机制的可能性； [C]确定E2如何调节p53和p38之间的动态； [d]通过详细介绍器官水平的心脏p38表达和激活的p53特异性变化，在整个I/R损伤的整个动物模型中翻译和确认发现。在特定的目标3中，我们将定义雌激素受体（ER）亚型在心肌细胞保护中的作用。我们怀疑两种ER亚型（ER¿和ER¿）对于以线粒体为中心的细胞凋亡中的全细胞保护是必不可少的。 We will [A] delineate how each receiver signals to p38¿ and subsequent regulation of oxidative stress in mitochondria [B] identify and characterize endogenous ER ¿ /¿ heterodimers in cardiomyocyte mitochondria, and [C] express a fusion ER ¿ /¿ protein in ER-null cells and compare with ER homodimers in its ability to regulate apoptosis, mitochondrial p53和p38功能。