IP3 receptor, NOX2 and calcium signaling domains in atrial physiology and pathophysiology

心房生理学和病理生理学中的 IP3 受体、NOX2 和钙信号传导域

• 批准号: 10597225
• 负责人: LOTHAR A BLATTER
• 金额: $ 67.35万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597225
• 关键词: Action Potentials; Arrhythmia; Atrial Fibrillation; Calcium; Calcium Signaling; Cardiac; Cardiovascular Diseases; Coupling; Data; Endowment; Functional disorder; Generations; Goals; Health Care Costs; Heart Atrium; Heart failure; ITPR1 gene; Inositol; Laboratories; Link; Mediating; Membrane; Mitochondria; Modeling; Morbidity - disease rate; Muscle Cells; NADPH Oxidase; Nuclear; Pacemakers; Peripheral; Physiological; Physiology; Pilot Projects; Play; Post-Translational Protein Processing; Predisposition; Process; Pump; Reactive Oxygen Species; Regulation; Risk; Role; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Sex Differences; Signal Transduction; Source; System; Testing; Tissues; Transcription Initiation; Transcriptional Regulation; Up-Regulation; Ventricular; Work; heart function; inorganic phosphate; mortality; nuclear factors of activated T-cells; receptor; release factor; response; sex; sexual dimorphism; spatiotemporal; transcription factor

PROJECT SUMMARY/ABSTRACT Atrial excitation-contraction coupling (ECC) and sarcoplasmic reticulum (SR) Ca release have unique features and are distinctly different from ventricular ECC. During ECC the action potential (AP) initiates Ca release from the SR Ca stores primarily through the ryanodine receptor (RyR) Ca release channels. The atrial SR has a second, albeit less abundant Ca release channel, the inositol-1,4,5-trisphosphate receptor (IP3R). IP3R induced Ca release (IICR) participates in ECC but also has non-ECC functions, including contribution to pacemaker activity, mitochondrial Ca signaling, and regulation of transcription factor activity important for pathophysiological atrial remodeling. IICR has sex-specific attributes and exerts positive inotropic effects, but also facilitates proarrhythmic Ca release. IICR is upregulated in atrial tissue in heart failure (HF), which facilitates SR Ca release and enhances atrial contraction, but also leads to increased risk of alternans and atrial fibrillation. The cardiac IP3R is target of post-translational modifications. New preliminary data demonstrate that in atrial myocytes the IP3R is co-regulated by IP3 and ROS provided by NADPH-oxidase type 2 (NOX2) and involves ROS-dependent IP3R glutathionylation. The overall goal of this proposal will test the hypothesis that in atrial tissue a NOX2/ROS/IP3R signaling domain is responsible for the positive inotropic and proarrhythmic effects of IICR, and to determine HF induced changes in ROS dependent IICR regulation and their consequences for atrial remodeling, alternans and atrial fibrillation (AF) risk. The 3 specific aims are: Specific aim 1: Define the mechanism of IP3R co-regulation by IP3 and ROS and determine its sex-specific attributes. We will test the hypotheses that IICR is co-regulated by IP3 and ROS in a defined NOX2/ROS/IP3R microdomain and that ROS dependent glutathionylation of IP3R modulates atrial Ca release during ECC. Alternative candidates of cellular ROS sources (mitochondria, NOX4) for IP3R modulation in addition to NOX2, and sex-specific attributes of ROS/IP3 co-regulation of IICR will be determined. Specific aim 2: Determine atrial remodeling of NOX2/ROS/IP3R signaling and its consequences for ECC, Ca release and transcription factor regulation in HF. We will test the hypothesis that in atrial tissue of a ventricular HF model ROS sources alternative to NOX2 upregulate IICR and thereby change its contribution to atrial Ca transient (CaT), contraction, and transcription factor (NFAT) activation through nuclear IP3Rs. Specific aim 3: Determine the mechanisms of ROS/IICR mediated increase in Ca alternans propensity and AF susceptibility in normal and HF atrial tissue. We will test the hypotheses that IICR facilitates pacing induced CaT alternans that is further enhanced in HF, and that synergistically ROS/IICR mediated alternans generates a substrate that increases the susceptibility for AF episodes.

项目概要/摘要 心房兴奋-收缩耦合 (ECC) 和肌浆网 (SR) Ca 释放具有独特的特征 与心室 ECC 明显不同。在 ECC 期间，动作电位 (AP) 启动 Ca 释放 SR Ca 主要通过兰尼碱受体 (RyR) Ca 释放通道储存。心房 SR 有一个 第二，尽管钙释放通道不太丰富，但肌醇-1,4,5-三磷酸受体（IP3R）。 IP3R诱导 Ca 释放 (IICR) 参与 ECC，但也具有非 ECC 功能，包括对起搏器的贡献 活性、线粒体 Ca 信号转导和转录因子活性的调节对于 病理生理学心房重构。 IICR 具有性别特异性属性并发挥正性肌力作用，但 也有利于促心律失常的 Ca 释放。 IICR 在心力衰竭 (HF) 的心房组织中表达上调，这 促进 SR Ca 释放并增强心房收缩，但也会导致交替糖和 心房颤动。心脏 IP3R 是翻译后修饰的目标。新的初步数据 证明在心房肌细胞中，IP3R 受到 IP3 和 NADPH 氧化酶类型提供的 ROS 的共同调节 2 (NOX2) 并涉及 ROS 依赖性 IP3R 谷胱甘肽化。该提案的总体目标将测试 假设在心房组织中，NOX2/ROS/IP3R 信号传导域负责正性肌力和 IICR 的致心律失常作用，并确定 HF 诱导的 ROS 依赖性 IICR 调节的变化和 它们对心房重构、交替和心房颤动 (AF) 风险的影响。 3个具体目标是： 具体目标1：明确IP3与ROS共同调控IP3R的机制并确定其性别特异性 属性。我们将测试 IICR 在定义的 NOX2/ROS/IP3R 中由 IP3 和 ROS 共同调节的假设 微结构域和 ROS 依赖性 IP3R 谷胱甘肽化在 ECC 期间调节心房 Ca 释放。 除 NOX2 之外，用于 IP3R 调节的细胞 ROS 来源（线粒体、NOX4）的替代候选者， IICR 的 ROS/IP3 共同调节的性别特异性属性将被确定。 具体目标 2：确定 NOX2/ROS/IP3R 信号传导的心房重塑及其对 ECC、Ca 的影响 HF 中的释放和转录因子调节。我们将检验以下假设：在心室的心房组织中 HF 模型 ROS 来源替代 NOX2 上调 IICR，从而改变其对心房 Ca 的贡献 通过核 IP3R 进行瞬时 (CaT)、收缩和转录因子 (NFAT) 激活。 具体目标 3：确定 ROS/IICR 介导的 Ca alternans 倾向增加的机制和 正常心房组织和心房组织中的房颤敏感性。我们将测试 IICR 促进起搏诱导的假设 CaT 交替糖在 HF 中进一步增强，并且协同 ROS/IICR 介导的交替糖产生 增加 AF 发作易感性的底物。