Targeting Metabo-Redox Network Vulnerability in Heart Failure and Sudden Death

针对心力衰竭和猝死中代谢氧化还原网络的脆弱性

• 批准号: 9522223
• 负责人: D Brian Foster
• 金额: $ 53.45万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9522223
• 关键词: Action Potentials; Acute; Affect; Animal Model; Animals; Arrhythmia; Automobile Driving; CREB1 gene; Cardiac; Cavia; Cell Death; Chronic; Congestive Heart Failure; Coupling; Cross-Over Studies; Data; Defibrillators; Diagnosis; Disease; EFRAC; Electrophysiology (science); Event; Experimental Models; Extracellular Matrix; Family; Feedback; Functional disorder; Future; Gene Proteins; Genes; Genetic Transcription; Goals; Heart failure; Homeostasis; Human; Impairment; Implantable Defibrillators; Incidence; Inflammation; Intervention; Ion Channel; Long QT Syndrome; MAPK14 gene; MAPK8 gene; Mediating; Metabolic; Mitochondria; Mitogen-Activated Protein Kinases; Modeling; Muscle Cells; Nature; Nuclear; Organ; Outcome; Oxidation-Reduction; Oxidative Stress; Pathway Analysis; Pathway interactions; Patients; Phenotype; Phosphoproteins; Phosphorylation; Physiology; Post-Translational Protein Processing; Prevalence; Process; Property; Proteins; Proteome; Proteomics; Protocols documentation; Qualifying; Reactive Oxygen Species; Regulation; Risk; Second Messenger Systems; Signal Pathway; Signal Transduction; Sudden Death; Telemetry; Testing; Time; Work; antioxidant enzyme; design; effective therapy; experimental study; human disease; improved; in vivo; inhibitor/antagonist; insight; member; mortality; multiple omics; novel therapeutics; palliative; prevent; programs; response; sudden cardiac death; therapeutic target

Heart failure (HF) is increasing in prevalence and incidence in the US. Despite advances in treatment, mortality is ~50% within 5 years of diagnosis with half of those deaths from sudden cardiac death (SCD), many before ejection fraction has decreased to a qualifying level for an implantable defibrillator (EF35%). There are no effective therapies to specifically treat SCD, apart from a defibrillator, which is palliative, not preventive. The multifactorial nature of HF/SCD requires an approach that considers the integrative physiology of both the myocyte and the organ, and a suitable experimental model with features of the human disease. This project leverages a unique guinea pig HF model that recapitulates many important aspects described in human heart failure, including long QT syndrome, arrhythmogenic SCD, inflammation, extracellular matrix remodeling, impaired Ca2+ handling, metabolic remodeling, and oxidative stress. Employing cellular experiments with a multi-omic approach, our recent and new data provides a comprehensive understanding of the genes, proteins, and fluxes (ionic and metabolic) behind the pathophysiology of HF/SCD. We identified important control points involved in acute emergent events, such as impaired metabo-redox coupling leading to mitochondrial ROS (mROS) overload and SCD, and those that mediate chronic remodeling, characterized by suppression of metabolic and redox transcriptional programs, lowering the threshold for the acute events. Our exciting preliminary data shows that both SCD and HF can be prevented or reversed by treatment with the mitochondrial ROS (mROS) scavenger, mitoTEMPO. For the first time, we show that mROS drives chronic remodeling of the specific phosphoproteome and the expression proteome in HF, likely through mitogen-activated protein (MAP) kinase activation. Remarkably, the design of our mROS scavenger protocol allows us to discriminate between mechanisms impacting SCD risk versus those that alter contractile function. Thus, the overarching goal of this application is to determine which proteins are targets of acute regulation by mROS, contributing to SCD/arrhythmia risk, versus those that are implicated in chronic HF remodeling. We hypothesize that mROS acutely impairs Ca2+ handling and repolarization, but also acts as a second messenger causing negative HF outcomes by disrupting the normal coupling between cytosolic signals and the nuclear gene programs driving mitochondrial function, antioxidant enzymes, Ca2+ handling and action potential repolarization and that the chronic effects of mROS are transduced through activation of MAP kinases. Our aims are to 1) determine protein/phosphoprotein targets regulated by mROS that discriminate between high arrhythmia/SCD risk and the HF state, 2) determine the acute versus chronic contribution of mROS to the electrophysiologic, EC-coupling and ROS abnormalities underlying SCD and HF in myocytes and intact animals, and 3) determine which branch of the MAP kinase family mediates the mROS-dependent uncoupling between cytoplasmic signals and proteome remodeling.

心力衰竭(HF)在美国的患病率和发病率正在增加。尽管在治疗方面取得了进展，但死亡率仍在上升 约50%在确诊后5年内死亡，其中一半死于心脏性猝死(SCD)，其中许多死于射血前 分数已降至植入式除颤器的合格水平(EF35%)。目前还没有有效的治疗方法 除了除颤器外，专门治疗SCD的是姑息性的，而不是预防性的。的多面性 HF/SCD需要一种考虑心肌细胞和器官的综合生理学的方法，并且 适合人类疾病特点的实验模型。该项目利用了一种独特的豚鼠HF模型 这概括了人类心力衰竭的许多重要方面，包括长QT综合征， 致心律失常的SCD，炎症，细胞外基质重塑，钙处理受损，代谢重塑， 和氧化应激。利用多组学方法进行细胞实验，我们最新和新的数据提供了 全面了解病理生理学背后的基因、蛋白质和通量(离子和代谢) 心衰/心绞痛。我们确定了与急性紧急事件有关的重要控制点，例如代谢-氧化还原受损 导致线粒体ROS(MRO)超载和SCD的偶联，以及那些介导慢性重构的偶联， 以抑制代谢和氧化还原转录程序为特征，降低急性 事件。 我们令人兴奋的初步数据表明，SCD和HF都可以通过使用 线粒体ROS清道夫，MitoTEMPO。我们第一次展示了MRO会导致慢性疾病 HF中特异的磷酸蛋白质组和表达蛋白质组的重构，可能是通过丝裂原激活的 蛋白(MAP)激酶激活。值得注意的是，我们的MROS清道夫协议的设计允许我们区分 影响SCD风险的机制与改变收缩功能的机制之间的关系。因此，总体目标是 这一应用是为了确定哪些蛋白质是MRO急性调节的目标，从而有助于 心源性心脏病/心律失常的风险，与那些与慢性心力衰竭重构有关的风险。我们准确地假设了MRO 损害钙离子的处理和复极，但也作为第二信使通过以下方式导致负性心力衰竭结果 破坏胞质信号与驱动线粒体的核基因程序之间的正常耦合 功能、抗氧化酶、钙离子处理和动作电位复极以及MROS的慢性影响 是通过激活MAP激酶进行转导的。我们的目标是1)确定蛋白质/磷蛋白靶标 由区分高心律失常/SCD风险和心力衰竭状态的MRO调节，2)确定 MRO对电生理、EC偶联和ROS异常的急性和慢性贡献 在心肌细胞和完整动物中潜在的SCD和HF，以及3)决定MAP激酶的哪一分支 家族介导胞质信号和蛋白质组重构之间依赖MROS的解偶联。