Cardiac KCNE2 (MIRP1) Regulation by Estrogen and Cardiac Stress

雌激素和心脏应激对心脏 KCNE2 (MIRP1) 的调节

基本信息

  • 批准号:
    8094521
  • 负责人:
  • 金额:
    $ 38.5万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2008
  • 资助国家:
    美国
  • 起止时间:
    2008-07-14 至 2013-04-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): KCNE2 is a single transmembrane modulatory ¿ subunit that in heterologous systems can modulate a variety of K channel pore-forming 1 subunits including Kv4.2 and Kv4.3, major components of fast transient outward K+ currents (Ito,f) in the heart. Highlighting its clinical relevance, KCNE2 inherited mutations are associated with human cardiac arrhythmogenesis and long QT syndrome. Recently Dr. Abbott in a personal communication informed me that KCNE2 knockout (KCNE2-/-) mice display a major reduction in Ito,f currents and a propensity to drug induced arrhythmogenesis. Further, we recently found that KCNE2, via a direct genomic mechanism, is activated by estrogen (E2), a well-known steroid hormone with cardioprotective properties in several species. In particular, in mouse, E2 treatment ameliorates the hypertrophic response to pressure overload by transaortic constriction (TAC). Thus, I decided to investigate whether E2- induced KCNE2 remodeling including its subcellular localization correlates with Ito,f changes and rescue from cardiac stress. Preliminary data indicates that: In non-stressed animals with high E2 cardiac KCNE2 transcript levels are dramatically upregulated. Strikingly, E2 favored KCNE2 localization in the T-tubules which should facilitate its association with T-tubular Kv a-subunits; while in TAC animals, E2 administration exerted a dramatic rescue from heart failure (HF) restoring ejection fraction and cardiac excitability together with KCNE2 transcript upregulation and protein redistribution to the T-tubular membrane. Thus, the general hypothesis postulates that: Heart E2 levels may upregulate KCNE2 transcript and protein levels, with targeting to the T-tubules favoring KCNE2 interaction with Kv4.3/Kv4.2 channels potentiating Ito,f currents. To test the overall hypothesis, a multidisciplinary approach will be used including molecular biology, biochemistry, electrophysiology and proteomics in conjunction with high-resolution confocal microscopy. The Specific Aims are 1) To determine in normal animals the mechanism(s) of estrogen-induced changes on the expression of Ito,f and IK,slow and functional consequences: role of Kv4.3/4.2 and Kv1.5 and auxiliary subunits (KCNE2 and KChIP2); and 2) To determine the mechanism(s) of estrogen-induced rescue of TAC induced heart failure. These studies will provide new information on KCNE2 and E2 roles in cardioprotection and cardiac excitability and provide molecular mechanisms to understand gender related differences in propensity to ventricular arrhythmias. PUBLIC HEALTH RELEVANCE: Females during the reproductive age have low incidence to heart disease when compared with males supporting the view that female hormones (estrogen) may have a protective action. However, the role of estrogen and the mechanisms involved are little understood. The goal of this project is to gain insight in how estrogen may induce cardioprotection by regulating the activity of a gene that is exquisitely modulated by estrogen and that modifies cardiac excitability.
描述(由申请人提供):KCNE 2是一种单跨膜调节亚基,在异源系统中可调节多种K通道孔形成亚基,包括Kv4.2和Kv4.3,心脏中快速瞬时外向K+电流(Ito,f)的主要组分。突出其临床相关性,KCNE 2遗传性突变与人类心肌梗死和长QT综合征相关。最近,Abbott博士在一次个人交流中告诉我,KCNE 2敲除(KCNE 2-/-)小鼠显示Ito,f电流显著降低,并倾向于药物诱导的肿瘤发生。此外,我们最近发现KCNE 2通过直接的基因组机制被雌激素(E2)激活,雌激素是一种众所周知的类固醇激素,在几个物种中具有心脏保护作用。特别地,在小鼠中,E2治疗通过经主动脉收缩(TAC)改善对压力超负荷的肥大反应。因此,我决定研究E2诱导的KCNE 2重塑,包括其亚细胞定位是否与Ito,f变化和心脏应激的救援相关。初步数据表明:在非应激动物与高E2心脏KCNE 2转录水平显着上调。引人注目的是,E2有利于KCNE 2在T-小管中的定位,这应该促进其与T-小管Kv α-亚基的结合;而在TAC动物中,E2给药对心力衰竭(HF)产生了显著的拯救作用,恢复射血分数和心脏兴奋性,以及KCNE 2转录上调和蛋白重新分布到T-小管膜。因此,一般假设假设:心脏E2水平可能上调KCNE 2转录和蛋白水平,靶向T-小管有利于KCNE 2与Kv4.3/Kv4.2通道相互作用,增强Ito,f电流。为了检验整体假设,将使用多学科方法,包括分子生物学,生物化学,电生理学和蛋白质组学,结合高分辨率共聚焦显微镜。具体目的是:1)在正常动物中确定雌激素诱导的Ito、f和IK表达变化的机制,缓慢和功能性后果:Kv4.3/4.2和Kv1.5以及辅助亚基(KCNE 2和KChIP 2)的作用; 2)确定雌激素诱导的TAC诱导的心力衰竭的补救机制。这些研究将为KCNE 2和E2在心脏保护和心脏兴奋性中的作用提供新的信息,并为了解室性心律失常倾向的性别差异提供分子机制。公共卫生关系:与男性相比,育龄女性心脏病的发病率较低,这支持了女性激素(雌激素)可能具有保护作用的观点。然而,雌激素的作用和所涉及的机制知之甚少。这个项目的目标是深入了解雌激素如何通过调节一个基因的活性来诱导心脏保护作用,该基因被雌激素精细地调节并改变心脏兴奋性。

项目成果

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Mansoureh Eghbali其他文献

Mansoureh Eghbali的其他文献

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{{ truncateString('Mansoureh Eghbali', 18)}}的其他基金

Role of intestinal inflammation in oxidized lipid induced pulmonary hypertension
肠道炎症在氧化脂质诱导的肺动脉高压中的作用
  • 批准号:
    10381356
  • 财政年份:
    2022
  • 资助金额:
    $ 38.5万
  • 项目类别:
Role of Chromosome Y gene, Uty, in protecting against Pulmonary Hypertension
Y 染色体基因 Uty 在预防肺动脉高压中的作用
  • 批准号:
    10310983
  • 财政年份:
    2021
  • 资助金额:
    $ 38.5万
  • 项目类别:
Role of Chromosome Y gene, Uty, in protecting against Pulmonary Hypertension
Y 染色体基因 Uty 在预防肺动脉高压中的作用
  • 批准号:
    10454301
  • 财政年份:
    2021
  • 资助金额:
    $ 38.5万
  • 项目类别:
Role of miR125 in pulmonary hypertension secondary to interstitial lung disease
miR125在间质性肺疾病继发性肺动脉高压中的作用
  • 批准号:
    10524037
  • 财政年份:
    2019
  • 资助金额:
    $ 38.5万
  • 项目类别:
Role of miR125 in pulmonary hypertension secondary to interstitial lung disease
miR125在间质性肺疾病继发性肺动脉高压中的作用
  • 批准号:
    10312768
  • 财政年份:
    2019
  • 资助金额:
    $ 38.5万
  • 项目类别:
Role of miR125 in pulmonary hypertension secondary to interstitial lung disease
miR125在间质性肺疾病继发性肺动脉高压中的作用
  • 批准号:
    9917602
  • 财政年份:
    2019
  • 资助金额:
    $ 38.5万
  • 项目类别:
Role of miR125 in pulmonary hypertension secondary to interstitial lung disease
miR125在间质性肺疾病继发性肺动脉高压中的作用
  • 批准号:
    10063562
  • 财政年份:
    2019
  • 资助金额:
    $ 38.5万
  • 项目类别:
Role of miR193 in oxidized lipid induced pulmonary hypertension
miR193在氧化脂质诱导的肺动脉高压中的作用
  • 批准号:
    9330227
  • 财政年份:
    2016
  • 资助金额:
    $ 38.5万
  • 项目类别:
Role of miR193 in oxidized lipid induced pulmonary hypertension
miR193在氧化脂质诱导的肺动脉高压中的作用
  • 批准号:
    9107288
  • 财政年份:
    2016
  • 资助金额:
    $ 38.5万
  • 项目类别:
Cardiac KCNE2 (MIRP1) Regulation by Estrogen and Cardiac Stress
雌激素和心脏应激对心脏 KCNE2 (MIRP1) 的调节
  • 批准号:
    7842057
  • 财政年份:
    2009
  • 资助金额:
    $ 38.5万
  • 项目类别:

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