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.

项目总结/摘要 心房兴奋-收缩偶联（ECC）和肌浆网（SR）钙释放具有独特的特点 并且与心室ECC明显不同。在ECC期间，动作电位（AP）启动Ca从 SRCa主要通过Ryanodine受体（RyR）Ca释放通道储存。心房SR具有 第二，虽然不太丰富的钙释放通道，肌醇-1，4，5-三磷酸受体（IP 3R）。IP 3R诱导 钙释放（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信号传导和转录因子活性的调节对于 病理生理性心房重构。IICR具有性别特异性属性，并发挥正性肌力作用，但 也促进促钙释放。IICR在心力衰竭（HF）的心房组织中上调， 促进SR Ca释放并增强心房收缩，但也导致交替的风险增加， 心房颤动心脏IP 3R是翻译后修饰的靶标。新的初步数据 证明在心房肌细胞中，IP 3R由IP 3和由NADPH氧化酶型提供的ROS共同调节 2（NOX 2），并涉及ROS依赖性IP 3R谷胱甘肽化。本提案的总体目标将检验 假设在心房组织中，NOX 2/ROS/IP 3R信号结构域负责正性肌力作用， IICR的预防作用，并确定HF诱导的ROS依赖性IICR调节的变化， 心房重构、电交替和房颤（AF）风险的后果。这三个具体目标是： 具体目标1：明确IP 3和ROS协同调节IP 3R的机制，并确定其性别特异性 美德.先知-愿我们将检验IICR在定义的NOX 2/ROS/IP 3R中由IP 3和ROS共同调节的假设。 在ECC期间，IP 3R的ROS依赖性谷胱甘肽化调节心房Ca释放。 除了NOX 2之外，用于IP 3R调节的细胞ROS源（线粒体，NOX 4）的替代候选物， 并确定IICR的ROS/IP 3共调节的性别特异性属性。 具体目标2：确定NOX 2/ROS/IP 3R信号传导的心房重构及其对ECC，Ca HF中转录因子的释放和调节。我们将检验一个假设，即在心室的心房组织中， HF模型ROS源替代NOX 2上调IICR，从而改变其对心房Ca ~（2+）的贡献 瞬时（CaT）、收缩和转录因子（NFAT）通过核IP 3R活化。 具体目标3：确定ROS/IICR介导的交替钙倾向增加的机制， 正常和HF心房组织的AF易感性。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ROS/IICR介导的交替糖协同产生 增加房颤发作易感性的基质。