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.

项目概要 ATF6 在粗糙的 ER 中感知到 ER 蛋白错误折叠，ATF6 在所有哺乳动物细胞中表达。我们 先前表明，在心室肌细胞中，体内缺血会导致 ER 蛋白错误折叠，即 被 ATF6 感知，将其转化为转录因子，诱导未知的抗氧化基因 在任何细胞类型中均受 ATF6 调节。我们的目标是研究 ATF6 作为关键元素的新作用 调节分泌，重点关注心房钠尿肽 (ANP)，这是一种在心房内质网中产生的肽激素 肌细胞。 ATF6 在心房中的功能及其在调节激素分泌中的作用均未得到证实。 研究过。因此，该提案提出了 ATF6 作为调节激素分泌关键的新作用 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 与心室细胞和组织相比，在应激条件下，心房细胞和组织中发现了活化的 ATF6， 即使没有 ER 应激。虽然激活的 ATF6 不会增加心房中的 ANP 基因表达，但 心房肌细胞分泌 ANP 是必需的。从机制上讲，我们发现 ATF6 诱导了几种 以前不知道 ATF6 调节的分泌途径蛋白，并且尚未在 心脏，包括 SNARE 蛋白 SNAP23。 SNAP23 已知可增强颗粒对接和分泌 在其他细胞类型中。基于此背景和初步数据，我们的假设是 ATF6 至关重要 促进 ANP 的分泌和对心血管 (CV) 的有益作用。 SNAP23 是两者之间的机械联系 ATF6 和调节 ANP 分泌。我们将通过三个具体目标来解决这一假设，即：1- 检查基于 AAV9 和小分子的 ATF6 功能获得以及条件 ATF6 基因的影响 对心房肌细胞和小鼠心脏的 ANP 分泌进行删除操作，2-确定 ATF6 如何获得- 功能丧失影响高盐饮食小鼠模型中的血浆 ANP 和血流动力学参数 诱发高血压和压力超负荷诱发心力衰竭，以及3-定义其机制作用 ATF6 诱导的分泌颗粒对接蛋白 SNAP23 在培养心房肌细胞 ANP 分泌中的作用 和老鼠的心。