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.

项目摘要/摘要 心房激发 - 收缩耦合（ECC）和肌质网（SR）CA释放具有独特的特征 并且与心室ECC明显不同。在ECC期间，动作电位（AP）启动了CA释放 SR CA主要通过Ryanodine受体（RYR）Ca释放通道存储。心房SR有一个 其次，尽管较少的CA释放通道，但肌醇1,4,5-三磷酸受体（IP3R）。 IP3R引起的 CA发布（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 病理生理心房重塑。 IICR具有特定性别的属性，并发挥积极的肌力作用，但 还促进了心律失常CA的释放。 IICR在心力衰竭（HF）的心房组织中上调，该组织 促进SR CA释放并增强心房收缩，但也导致替代品的风险增加 心房颤动。心脏IP3R是翻译后修饰的目标。新的初步数据 证明在心房心肌细胞中IP3R由IP3和NADPH-氧化酶类型提供的ROS共同调节 2（NOX2），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信号传导域是阳性肌力和 IICR的心律失常，并确定HF诱导的ROS依赖性IICR调节的变化和 它们对心房重塑，替代品和房颤（AF）风险的后果。 3个具体目标是： 特定目标1：定义IP3和ROS共同调节IP3R的机制，并确定其性别特定的性别 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 微域和IP3R的ROS依赖性谷胱甘肽化在ECC期间调节心房CA释放。 除NOX2外 ROS/IP3共同调节IICR的性别特异性属性将被确定。 特定目标2：确定NOX2/ROS/IP3R信号传导及其对ECC的后果的心房重塑 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IP3RS激活瞬态（CAT），收缩和转录因子（NFAT）。 特定目标3：确定ROS/IICR的机制介导的CA替代品倾向的增加和 正常和HF心房组织中的AF敏感性。我们将检验IICR促进起搏引起的假设 HF进一步增强的猫替代品，该协同ROS/IICR介导的替代品会生成 一种增加AF发作易感性的底物。