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 ATF6在粗糙的ER中检测到ER蛋白的折叠率错折叠，这在所有哺乳动物细胞中均表达。我们 以前表明，在体内的心肌细胞中，缺血会导致ER蛋白质折叠，这是 通过ATF6感应，将其转化为转录因子，该转录因子诱导抗氧化基因 在任何细胞类型中都受到ATF6调节。我们的目的是研究ATF6作为关键要素的新角色 受调节的分泌，重点放在心房尿液肽（ANP）上 心肌细胞。 ATF6在心房中的功能既不是其在受调节激素分泌中的作用 研究。因此，该提案解决了ATF6作为linchpin的新作用 使用我们称为ATF6-ANP轴的心脏模型系统。我们的初步数据表明，在非 - 与心室细胞和组织相反，应力条件在心房细胞和组织中发现了ATF6， 即使没有ER应力。虽然激活的ATF6并未增加心房中的ANP基因表达，但 是对心肌细胞的ANP分泌所必需的。从机械上讲，我们发现ATF6诱导了几个 分泌途径蛋白以前尚不知道ATF6调节且尚未在 心脏，包括军鼓蛋白，snap23。已知SNAP23可以增强颗粒对接和分泌物 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是必不可少的 对于ANP的分泌和有益的心血管（CV）效应。 SNAP23是一种机械联系 ATF6并规范ANP分泌。我们将以三个特定目标来解决这一假设，该假设是：1- 检查基于AAV9和小分子的ATF6功能获得的效果，以及条件ATF6基因 从心肌细胞和小鼠心脏分泌ANP分泌的删除操作，2确定ATF6如何增益 - 功能丧失会影响血浆ANP和血液动力学参数 诱导的高血压和压力超负荷引起的心力衰竭，三定义 ATF6诱导的分泌颗粒对接蛋白Snap23在培养的心房肌细胞的ANP分泌中 和鼠标的心。