Redox Modification of the Arrhythmic Substrate in Heart Failure

心力衰竭中心律失常基质的氧化还原修饰

基本信息

批准号：
8242675
负责人：
Brian O'Rourke
金额：
$ 74.94万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8242675
关键词：
Accounting Action Potentials Adrenergic Agents Affect Anabolism Angiotensins Antioxidants Arrhythmia Biology Calculi Cardiac Cavia Cell Death Cells Cessation of life Communication Computer Simulation Couples Coupling Cytoplasm Data Diagnosis Disease Elderly Electrophysiology (science)Energy Metabolism Environment Equilibrium FADH2 Failure Fibrosis Glutathione Disulfide Goals Heart Heart Hypertrophy Heart Mitochondria Heart failure Homeostasis Individual Inpatients Ion Channel Ions Lead Measurement Mediating Membrane Metabolic Metabolic stress Metabolism Mitochondria Modeling Modification Morbidity - disease rate Muscle Cells NADH NADP Oxidation-Reduction Oxidative Stress Pathology Pathway interactions Performance Post-Translational Protein Processing Predisposition Prevalence Process Production Property Pump Reactive Oxygen Species Renin Sarcoplasmic Reticulum Signal Pathway Signal Transduction Structure Sulfhydryl Compounds System Systems Biology Testing Therapeutic Intervention TimeLine Tissues United States adrenergic base economic impact heart function inhibitor/antagonist mortality pressure public health relevance research study response sudden cardiac death

项目摘要

DESCRIPTION (provided by applicant): Heart failure is a disease that is continually increasing in prevalence worldwide. In the United States, nearly 6 million people suffer from heart failure and it is the most common inpatient diagnosis in the elderly. The economic impact for 2009 has been estimated at $37.2 billion. Treatment of this disease with 2-blockers and/or inhibitors of renin-angiotensin signaling has decreased mortality and morbidity over the years, but mortality still approaches 60% within 5 years of diagnosis. Fatal arrhythmias, known as Sudden Cardiac Death (SCD), account for about half of the early deaths in HF, with progressive cardiac decompensation accounting for the remainder. Many factors contribute to the pathology of HF, including changes in the neurohumoral environment, alterations in ion channel and transporter activity, modulation of cell death pathways, and remodeling of the inherent structure of the tissue. Recent evidence indicates that alterations in the reduction- oxidation (redox) potential of the cytoplasm, sarcoplasmic reticulum, and the mitochondria of the heart may be a key factor involved in the progression of cardiac hypertrophy and failure. In heart failure (HF), there is evidence that oxidative stress may contribute to impaired function, and this may arise as a consequence of altered ion homeostasis, energetic deficiencies, and post-translational modification of protein targets. Moreover, a large number of ion channels, transporters, and signaling pathways have been shown to be modulated either directly by reactive oxygen species (ROS), or by changes in the thiol status or redox carrier concentration. Some, or many, of these targets, could contribute to an enhanced susceptibility of the failing heart to arrhythmogenesis and SCD. A comprehensive view of how shifts in metabolism and redox balance influence the electrophysiological substrate requires a systems biology approach to the problem, involving deconstruction of how individual ion channels, transporters and signaling pathways are affected by redox modulators, and how the performance of the integrated system is changed. Specifically, in this proposal, our objective is to examine how enhanced oxidative stress alters the electrophysiology, Ca2+ regulatory processes, and arrhythmia susceptibility of myocytes from failing hearts (pressure-overload model). An iterative, experimental/computational systems biology approach combining both "horizontal" and "vertical" integration will be taken. These approaches will be used to build biophysically-detailed cellular and whole-heart models of redox/antioxidant pathways and their downstream effects on ion channels and transporters, with the goal of defining how metabolic and oxidative stress leads to arrhythmias, pump failure, and SCD. An overriding goal will be to define the specific alterations that have the greatest influence on whole heart function, so as to narrow down the number of targets to pursue for therapeutic intervention. PUBLIC HEALTH RELEVANCE: Narrative Heart failure is a disease that is continually increasing in prevalence worldwide. In this proposal, our objective is to examine how enhanced oxidative stress alters the electrophysiology, Ca2+ regulatory processes, and arrhythmia susceptibility of myocytes from failing hearts. An overriding goal will be to define the specific alterations that have the greatest influence on whole heart function, so as to narrow down the number of targets to pursue for therapeutic intervention to treat heart failure.

描述（由申请人提供）：心力衰竭是一种在世界范围内患病率不断增加的疾病。在美国，有近 600 万人患有心力衰竭，这是老年人中最常见的住院诊断。 2009 年的经济影响估计为 372 亿美元。多年来，用 2-阻滞剂和/或肾素-血管紧张素信号传导抑制剂治疗这种疾病已降低死亡率和发病率，但诊断后 5 年内死亡率仍接近 60%。致命性心律失常，即心脏性猝死 (SCD)，约占心力衰竭早期死亡的一半，其余则为进行性心脏代偿失调。许多因素导致心力衰竭的病理学，包括神经体液环境的变化、离子通道和转运蛋白活性的改变、细胞死亡途径的调节以及组织固有结构的重塑。最近的证据表明，心脏细胞质、肌浆网和线粒体的氧化还原电位的改变可能是心脏肥大和衰竭进展的关键因素。在心力衰竭 (HF) 中，有证据表明氧化应激可能导致功能受损，这可能是离子稳态改变、能量缺乏和蛋白质靶标翻译后修饰的结果。此外，大量的离子通道、转运蛋白和信号传导途径已被证明可以直接受到活性氧（ROS）的调节，或者通过硫醇状态或氧化还原载体浓度的变化进行调节。这些目标中的一些或许多可能会导致衰竭心脏对心律失常和 SCD 的易感性增加。要全面了解代谢和氧化还原平衡的变化如何影响电生理底物，需要采用系统生物学方法来解决该问题，包括解构单个离子通道、转运蛋白和信号传导途径如何受到氧化还原调节剂的影响，以及集成系统的性能如何被改变了。具体来说，在本提案中，我们的目标是研究增强的氧化应激如何改变心衰心肌细胞的电生理学、Ca2+调节过程和心律失常易感性（压力过载模型）。将采用结合“水平”和“垂直”整合的迭代、实验/计算系统生物学方法。这些方法将用于建立氧化还原/抗氧化途径及其对离子通道和转运蛋白的下游影响的生物物理详细细胞和全心脏模型，目的是确定代谢和氧化应激如何导致心律失常、泵衰竭和 SCD 。首要目标是确定对整个心脏功能影响最大的具体改变，以缩小治疗干预的目标数量。公共卫生相关性：叙述心力衰竭是一种在世界范围内患病率不断增加的疾病。在本提案中，我们的目标是研究增强的氧化应激如何改变心力衰竭心肌细胞的电生理学、Ca2+调节过程和心律失常易感性。首要目标是确定对整个心脏功能影响最大的具体改变，以缩小心力衰竭治疗干预的目标数量。