Oxidative Stress, PKC Signaling and Heart Failure

氧化应激、PKC 信号传导和心力衰竭

• 批准号: 9029006
• 负责人: Long-Sheng Song
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9029006
• 关键词: Affect; Aging; American; Animal Model; Antioxidants; Architecture; Biological Preservation; Calcineurin; Calpain; Cardiac; Cardiac Myocytes; Cardiomyopathies; Caring; Clinical Trials; Coupling; Data; Development; Disease Progression; Dissection; Dominant-Negative Mutation; Down-Regulation; Electrophysiology (science); Event; Failure; Functional disorder; Goals; Health; Healthcare Systems; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Heat shock proteins; Human; Hypertrophy; Image; Impairment; In Situ; Link; Measures; Mediating; Membrane; Mitochondria; Modeling; Molecular Biology; Mouse Protein; Muscle Cells; Muscle Contraction; Myocardial; Myocardial dysfunction; NADPH Oxidase; Organ; Outcome; Oxidative Stress; PRKCA gene; Pathway interactions; Patient-Focused Outcomes; Patients; Peptide Hydrolases; Pilot Projects; Play; Protein Kinase C; Protein Kinase C Inhibitor; Publishing; Quality of life; Reactive Oxygen Species; Reagent; Reporting; Resources; Role; Sarcoplasmic Reticulum; Signal Transduction; Solid; Source; Stress; Structural Genes; Structure; Subcellular structure; System; Testing; Therapeutic; Transgenic Mice; Veterans; Work; base; cost; design; improved; inhibitor/antagonist; insight; interdisciplinary approach; junctophilin; membrane excitation; mortality; mouse model; novel; novel therapeutics; pressure; prevent; protein expression; public health relevance; response; stress protein; treatment strategy

 DESCRIPTION (provided by applicant): Heart failure is the number one reason for discharge for Veterans treated in VA health care system. Heart failure, measured at the organ level, is the result of cellular failure due to impairment of cardiac excitation-contraction (E-C) coupling. One key structural component of E-C coupling is the myocyte transverse (T)-tubule system. T-tubules play essential roles in membrane excitation, coordinated and synchronized activation of sarcoplasmic reticulum (SR) Ca2+ release, and muscle contraction. In failing myocytes from animal models and human patients, we and others have shown that the regularly arrayed T-tubule system undergoes disruptive remodeling, leading to aberrant intracellular Ca2+ release and compromised myocyte contractility. Our recently published data strongly suggest that T-tubule structural integrity is a critical structural determinant of myocardial contractile function. Moreover, we found that loss of protein expression of junctophilin-2 (JP2), a structural protein spanning T-tubules and the SR membrane, is a causative factor in T-tubule deformation in heart disease. Substantial evidence demonstrates that E-C coupling is impaired by oxidative stress, which is elevated in cardiomyocytes in heart disease. Despite the clear role for oxidative stress in cardiomyopathies, antioxidant trials in humans have failed to provide a therapeutic benefit, suggesting an incomplete understanding of oxidative stress-mediated pathways in heart disease or possibly wrong antioxidant strategy used in previous clinical trials. Previous reports have provided solid evidence that protein kinase C (PKC) is activated by oxidative stress. At the cellular level, PKC has been shown to impair E-C coupling. In pilot studies, activation of PKC resulted in alterations in cardiomyocyte structure and function. However, in order to identify new treatment strategies for heart disease that preserve cardiac contractility, there is a critical need to determine the mechanism by which PKC activation by oxidative stress induces E-C coupling dysfunction. The objective/goal of this application is to determine the mechanistic link between excessive oxidative stress, PKC signaling, and development and progression of heart failure. We will combine multidisciplinary approaches including in situ confocal imaging, electrophysiology, molecular biology, pathological mouse models and novel transgenic mouse models to test our hypothesis. Accomplishment of our studies will advance our understanding and provide new insights into the mechanisms of oxidative stress-mediated PKC activation and T-tubule remodeling in heart failure pathophysiology and is expected to have an important positive impact by revealing new targets for heart failure therapeutics. Given that over the last decade the number of resources used to treat heart failure within the VA health care system has grown steadily, new treatments that both improve patient outcomes and reduce the cost of care associated with heart failure will provide significant benefit to the VA health care system.

 描述（由申请人提供）： 心力衰竭是在退伍军人管理局医疗保健系统中接受治疗的退伍军人退伍的首要原因。在器官水平上测量的心力衰竭是由于心脏兴奋-收缩（E-C）耦合受损而导致细胞衰竭的结果。 E-C 耦合的关键结构组成部分之一是肌细胞横管 (T) 管系统。 T 管在膜激发、肌浆网 (SR) Ca2+ 释放的协调和同步激活以及肌肉收缩中发挥着重要作用。在来自动物模型和人类患者的衰竭肌细胞中，我们和其他人已经证明，规则排列的 T 管系统经历破坏性重塑，导致异常的细胞内 Ca2+ 释放和受损的肌细胞收缩力。我们最近发表的数据强烈表明 T 管结构完整性是一个 心肌收缩功能的关键结构决定因素。此外，我们发现损失 junctophilin-2 (JP2) 是一种跨越 T 管和 SR 膜的结构蛋白，其蛋白表达是心脏病 T 管变形的致病因素。大量证据表明，E-C 耦合会受到氧化应激的损害，氧化应激在心脏病患者的心肌细胞中会升高。尽管氧化应激在心肌病中发挥着明确的作用，但人体抗氧化试验未能提供治疗益处，这表明对心脏病中氧化应激介导的途径的了解不完全，或者以前的临床试验中可能使用了错误的抗氧化策略。之前的报告提供了确凿的证据表明蛋白激酶 C (PKC) 是由氧化应激激活的。在细胞水平上，PKC 已被证明会损害 E-C 耦合。在初步研究中，PKC 的激活导致心肌细胞结构和功能的改变。然而，为了确定保留心肌收缩力的心脏病新治疗策略，迫切需要确定氧化应激引起的 PKC 激活诱导 E-C 偶联功能障碍的机制。本申请的目的/目标是确定过度氧化应激、PKC 信号传导与心力衰竭的发生和进展之间的机制联系。我们将结合多学科方法，包括原位共聚焦成像、电生理学、分子生物学、病理小鼠模型和新型转基因小鼠模型来检验我们的假设。我们研究的完成将增进我们对心力衰竭病理生理学中氧化应激介导的 PKC 激活和 T 管重塑机制的理解并提供新的见解，并有望通过揭示心力衰竭治疗的新靶点产生重要的积极影响。鉴于在过去十年中，退伍军人管理局医疗保健系统内用于治疗心力衰竭的资源数量稳步增长，既能改善患者治疗效果并降低与心力衰竭相关的护理成本的新疗法将为退伍军人管理局医疗保健系统带来显着效益。