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

• 批准号: 8402615
• 负责人: Brian O'Rourke
• 金额: $ 73.84万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 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/8402615
• 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

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.

描述（由申请人提供）：心力衰竭是一种在全球范围内不断增加的疾病。在美国，近600万人患有心力衰竭，这是老年人最常见的住院诊断。 2009年的经济影响估计为372亿美元。多年来，用2块阻滞剂和/或肾素 - 血管紧张素信号传导的抑制剂治疗这种疾病的死亡率和发病率降低，但在诊断后的5年内，死亡率仍然接近60％。致命性心律不齐，称为心脏猝死（SCD），约占HF早期死亡的一半，其余的心脏代偿负债累累。许多因素有助于HF的病理，包括神经肿瘤环境的变化，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，细胞质，肌质网和心脏线粒体的还原氧化（氧化还原）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有助于功能受损，这可能是由于离子稳态改变，能量性缺陷和蛋白质靶标的翻译后修饰而产生的。此外，已经显示出大量的离子通道，转运蛋白和信号通路是通过活性氧（ROS）或硫代氧载体浓度的变化直接调节的。其中一些或多个目标可能导致心律失常发生和SCD的心脏失败的敏感性增强。对新陈代谢和氧化还原平衡如何影响电生理底物的全面看法需要采用系统生物学方法来解决该问题，涉及解构单个离子通道，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，以及如何更改集成系统的性能。具体而言，在此提案中，我们的目标是研究增强的氧化应激如何改变电生理学，CA2+调节过程和心律失常的心律失常敏感性（压力超负荷模型）。将采用一种迭代，实验/计算系统生物学方法，结合了“水平”和“垂直”整合。这些方法将用于构建氧化还原/抗氧化剂途径的生物物理详细细胞和全心模型及其对离子通道和转运蛋白的下游影响，目的是定义代谢和氧化应激如何导致心律失常，泵失败，泵失败和SCD。一个压倒性的目标是定义对整个心脏功能影响最大的特定变化，以缩小追求治疗干预的目标数量。