ATF6 is Required for ANP Secretion from the Heart

ATF6 是心脏分泌 ANP 所必需的

• 批准号: 10219762
• 负责人: Chris Glembotski
• 金额: $ 34.54万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-15 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10219762
• 关键词: ATF6 gene; Acute; Address; Adult; Affect; Antioxidants; Atrial Natriuretic Factor; Biological Models; Blood Pressure; Blood Volume; Calcium; Cardiac; Cardiac Myocytes; Cardiovascular Physiology; Cardiovascular system; Cell Nucleus; Cell membrane; Cells; Cessation of life; Chronic; Cleaved cell; Coupled; Cytoplasmic Granules; Data; Development; Docking; Elements; Ensure; Excretory function; Foundations; Gene Deletion; Gene Expression; Genes; Goals; Golgi Apparatus; Growth Factor Receptors; Heart; Heart Atrium; Heart failure; Hormone secretion; Hormones; Hypertension; Ion Channel; Ischemia; Link; Mammalian Cell; Mission; Modeling; Morbidity - disease rate; Mus; Muscle Cells; Organ; Oxidative Stress; Pathologic; Pathway interactions; Plasma; Play; Proteins; Public Health; Quality Control; Research; Role; Rough endoplasmic reticulum; Route; SNAP receptor; SNAP23 gene; Secretory Vesicles; Site; Stretching; Time; Tissues; Transgenic Mice; United States National Institutes of Health; Vasodilation; Ventricular; base; cardiovascular effects; cell type; design; dietary; endoplasmic reticulum stress; gain of function; hemodynamics; in vivo; innovation; loss of function; misfolded protein; mortality; mouse model; novel; novel strategies; novel therapeutics; peptide hormone; pressure; programs; protein folding; protein function; protein misfolding; salt sensitive hypertension; small molecule; transcription factor; transcriptome

Project Summary ER protein misfolding is sensed in the rough ER by ATF6, which is expressed in all mammalian cells. We previously showed that in ventricular myocytes, in vivo, ischemia causes ER protein misfolding, which is sensed by ATF6, converting it to a transcription factor that induces antioxidant genes that were not known to be ATF6-regulated in any cell type. Our objective here is to study a new role for ATF6 as a critical element in regulated secretion, focusing on atrial natriuretic peptide (ANP), a peptide hormone made in the ER of atrial myocytes. Neither the function of ATF6 in the atria, nor its role in regulated hormone secretion has been studied. Therefore, this proposal addresses a novel role for ATF6 as a linchpin in regulated hormone secretion using a cardiac model system that we call the ATF6-ANP axis. Our preliminary data showed that under non- stressed conditions, in contrast to ventricular cell and tissue, activated ATF6 was found in atrial cell and tissue, even in the absence of ER stress. While activated ATF6 did not increase ANP gene expression in the atria, it was required for ANP secretion from atrial myocytes. Mechanistically, we found that ATF6 induced several secretory pathway proteins that were not previously known to be ATF6-regulated and have not been studied in the heart, including the SNARE protein, SNAP23. SNAP23 is known to enhance granule docking and secretion in other cell types. Based on this background and preliminary data, our hypothesis is that ATF6 is essential for the secretion and beneficial cardiovascular (CV) effects of ANP. SNAP23 is a mechanistic link between ATF6 and regulated ANP secretion. We will address this hypothesis in three specific aims, which are to: 1- examine the effects of AAV9- and small molecule-based ATF6 gain-of-function, and conditional ATF6 gene deletion maneuvers on ANP secretion from atrial myocytes and mouse hearts, 2-determine how ATF6 gain- and loss-of-function affects plasma ANP and hemodynamic parameters in mouse models of dietary high-salt- induced hypertension and pressure overload-induced heart failure, and 3-define the mechanistic role of the ATF6-inducible secretory granule docking protein, SNAP23, in ANP secretion from cultured atrial myocytes and mouse hearts.

项目摘要 ER蛋白的错误折叠是由ATF6在粗略的ER中检测到的，它在所有哺乳动物细胞中都有表达。我们 先前研究表明，在活体的心室肌细胞中，缺血会导致ER蛋白的错误折叠，这是 被ATF6感知，将其转换为转录因子，诱导未知的抗氧化基因 在任何细胞类型中都受ATF6调控。我们在这里的目标是研究ATF6作为一个关键元素在 调节分泌，重点是心房利钠肽(ANP)，这是一种在心房内质网中产生的多肽激素 肌细胞。无论是ATF6在心房中的功能，还是它在调节激素分泌中的作用，都没有得到 学习。因此，这项建议解决了ATF6作为调节激素分泌的关键的新角色。 使用我们称为ATF6-ANP轴的心脏模型系统。我们的初步数据显示，在非 应激状态下，与心室细胞和组织相比，ATF6在心房细胞和组织中被激活， 即使在没有内质网压力的情况下。虽然激活的ATF6不会增加心房中ANP基因的表达，但它 是心房肌细胞分泌ANP所必需的。从机制上讲，我们发现ATF6诱导了几个 分泌途径蛋白以前不知道是ATF6调节的，也没有研究过 心脏，包括SNARE蛋白，SNAP23。已知SNAP23可促进颗粒对接和分泌 在其他细胞类型中。基于这一背景和初步数据，我们的假设是ATF6是必不可少的 对于ANP的分泌和有益的心血管(CV)作用。SNAP23是一种机械连接， ATF6和调节ANP的分泌。我们将在三个具体目标中解决这个假设，这三个目标是：1- 检测基于AAV9和小分子的ATF6功能增益和条件性ATF6基因的作用 删除操作对心房肌细胞和小鼠心脏ANP分泌的影响，2-决定ATF6如何获得- 而功能丧失影响高盐饮食小鼠模型的血浆ANP和血流动力学参数。 诱发性高血压和压力超负荷引起的心力衰竭，以及3-定义 ATF6诱导的心房肌细胞分泌心钠素的分泌颗粒对接蛋白SNAP23 还有老鼠的心。