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
• 负责人: Mansoureh Eghbali
• 金额: $ 24.75万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7842057
• 关键词: Abbreviations; Action Potentials; Address; Age; Anabolism; Animals; Antibodies; Aromatase; Arrhythmia; Biochemistry; Cardiac; Cardiac Myocytes; Caveolins; Confocal Microscopy; Correlative Study; Data; Diffusion; Down-Regulation; Doxycycline; EFRAC; Echocardiography; Electrocardiogram; Electrophysiology (science); Estradiol; Estrogen Receptors; Estrogens; Estrus; Female; Figs - dietary; Gender; Gene Family; Genes; Genetic Transcription; Genetically Engineered Mouse; Genomics; Goals; Heart; Heart Diseases; Heart failure; Homologous Gene; Hormones; Human; Immunoprecipitation; Incidence; Inherited; Ion Channel; Kinetics; Knock-out; Kv channel-interacting protein 2; Kv4.2 channel; Lead; Long QT Syndrome; Mediating; Membrane; Mink; Modeling; Molecular; Molecular Biology; Mus; Mutation; Names; Operon; Peptides; Personal Communication; Pharmaceutical Preparations; Phenotype; Plasma; Potassium Channel; Proestrus; Property; Proteins; Proteomics; Proto-Oncogene Proteins c-akt; Radioimmunoassay; Regulation; Reporting; Resolution; Role; Shapes; Signal Pathway; Staging; Stress; Surface; System; Testing; Tetanus Helper Peptide; Tetracycline Control; Time; Trans-Activators; Transcript; Tubular formation; Up-Regulation; Ventricular Arrhythmia; Western Blotting; caveolin-3; clinically relevant; constriction; immunocytochemistry; insight; interdisciplinary approach; male; morphometry; mouse model; non-genomic; pressure; public health relevance; reproductive; response; restoration; steroid hormone

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）：KCNE2 是一种单跨膜调节剂 ¿ KCNE2 是一个亚基，在异源系统中可以调节多种 K 通道成孔 1 亚基，包括 Kv4.2 和 Kv4.3，它们是心脏中快速向外瞬时 K+ 电流 (Ito,f) 的主要组成部分，KCNE2 具有遗传性，突出了其临床相关性。突变与人类心律失常和长 QT 综合征有关。最近 Abbott 博士在一次个人通讯中告诉我，KCNE2 基因敲除 (KCNE2-/-) 小鼠表现出Ito,f 电流大幅减少和药物诱导心律失常的倾向此外，我们最近发现 KCNE2 通过直接基因组机制被雌激素 (E2) 激活，雌激素是一种在多个物种中具有心脏保护特性的众所周知的类固醇激素。特别是，在小鼠中，E2 治疗通过主动脉收缩 (TAC) 改善了对压力超负荷的肥大反应，因此，我决定研究 E2 是否诱导 KCNE2 重塑。初步数据表明：在具有高 E2 心脏的非应激动物中，KCNE2 转录水平显着上调，E2 有利于 KCNE2 在 T 管中的定位。促进其与 T 管 Kv a 亚基的关联，而在 TAC 动物中，E2 给药对心力衰竭 (HF) 具有显着的缓解作用，恢复射血分数和心脏功能；兴奋性以及 KCNE2 转录物上调和蛋白质重新分布到 T 管膜因此，一般假设假设：心脏 E2 水平可能上调 KCNE2 转录物和蛋白质水平，靶向 T 管有利于 KCNE2 与 Kv4.3/ 的相互作用。 Kv4.2 通道增强 Ito,f 电流 为了检验总体假设，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与高分辨率共聚焦显微镜相结合的具体目标是 1) 确定正常动物中雌激素诱导的 Ito、f 和 IK 表达变化的机制，缓慢和功能性后果：Kv4 的作用。 3/4.2和Kv1.5以及辅助亚基（KCNE2和KChIP2）；和2)确定雌激素拯救TAC诱导的心脏的机制。这些研究将提供有关 KCNE2 和 E2 在心脏保护和心脏兴奋性中的作用的新信息，并提供室性心律失常倾向的性别相关差异的分子机制。 公共健康相关性：相比之下，育龄女性了解心脏病的发生率较低。男性支持女性荷尔蒙（雌激素）可能具有保护作用的观点，但是，人们对雌激素的作用及其所涉及的机制知之甚少。雌激素如何通过调节基因的活性来诱导心脏保护，该基因受到雌激素的精细调节并改变心脏的兴奋性。