Frequency-dependent modulation of cardiac myofilament function in health/disease

健康/疾病中心肌丝功能的频率依赖性调节

• 批准号: 8893128
• 负责人: PAULUS ML JANSSEN
• 金额: $ 37.55万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2016-08-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8893128
• 关键词: Acute; Address; Behavior; Calcium; Cardiac; Cardiac Output; Chronic; Complex; Dependency; Development; Disease; Event; Exercise; Exhibits; Frequencies; Functional disorder; Future; Health; Health Transition; Heart; Heart Rate; Heart failure; Hour; Human; Hypertrophy; Kinetics; Life; Maintenance; Mechanics; Mediating; Microfilaments; Modeling; Modification; Molecular; Muscle; Myocardium; Nutrient; Oryctolagus cuniculus; Outcome Study; Output; Oxygen; Patients; Phenotype; Phosphorylation; Phosphotransferases; Play; Post-Translational Protein Processing; Preparation; Process; Property; Proteins; Proteomics; Protocols documentation; Publishing; Pulmonary artery structure; Randomized; Regulation; Relative (related person); Relaxation; Role; Series; Speed; Staging; Stroke Volume; System; Time; Tissues; Training; Work; base; disease phenotype; human tissue; novel; research study; response; temporal measurement

DESCRIPTION (provided by applicant): Maintenance of sufficient cardiac output to provide the body and the heart itself with nutrients and oxygen is a must to sustain life. To accomplish increase output, heart rate goes up significantly, and the specific force generated by the myocardium increases as well, boosting stroke volume. The latter phenomenon is known as the force-frequency relationship (FFR). In recent studies we observed that in rabbits, which display a similar FFR behavior as humans, not only is calcium handling involved in the FFR but post-translational modification of myofilament proteins occurs too, resulting in a frequency-dependent decrease in myofilament calcium sensitivity. This latter finding can at least partially explain the increased contractile kinetics, and explains how the heart can maintain a low diastolic tension despite significantly elevated intracellular calcium levels that prevail at high pacing rates, and may also play a prominent role in the FFR. In heart failure, the positive FFR is severely blunted or even becomes negative, and relaxation is impaired, these are classic hallmarks of this disease. A further understanding of frequency-dependent myofilament processes and modification is therefore paramount in understanding cardiac pathophysiology. Several central questions remain to be resolved in this emerging field. What is the relative contribution of the calcium transient and myofilament properties on frequency-dependent force and kinetics? What are the kinases involved, and what are the myofilament targets of these kinases regarding the FFR? To what extent are the myofilament-based contributions different in hypertrophy and heart failure? What is the sequence of events that leads to the disease's phenotype? Based on our previous work and current preliminary experiments, we have formulated the hypothesis that myofilament-based frequency-dependent regulation is mediated via kinase-mediated phosphorylation, and that this process is deranged in hypertrophy and heart failure. We will address our hypothesis in two rabbit model that exhibits FFR behavior very close to human in both aspects of calcium handling and myofilament composition and properties, as well as in non-failing and failing human tissue via 4 specific aims: 1) Dissect the temporal resolution of the force-frequency relationship, 2) Mechanistically dissect the myofilament-based protein targets and kinase-dependent process that are involved in the FFR. 3) Assess alterations in frequency- dependent activation in human heart failure tissue, and in a rabbit model of hypertrophy, and 4) Correlate and dissect functional and molecular changes in the FFR during the transition from healthy to failing myocardium in a novel muscle culture system. Combined, the outcome of this study will provide critical new information on a central deficit in function in patients with heart failure, and will allow us to strategize future treatment options.

描述（由申请人提供）：维持足够的心输出量，为身体和心脏本身提供营养，氧气是维持生命的必要条件。为了实现增加产量，心率显着提高，心肌产生的特定力也增加，从而增加了中风量。后一种现象被称为力频关系（FFR）。在最近的研究中，我们观察到，在表现出与人类类似的FFR行为的兔子中，不仅钙处理涉及FFR，而且在翻译后的肌丝蛋白也会发生，从而导致肌膜钙敏感性的频率依赖性降低。后一个发现至少可以部分解释 收缩动力学增加了，并解释了心脏如何保持较低的舒张压张力，尽管细胞内钙水平显着升高，并且在高起色率下占据了良好的水平，并且在FFR中也可能发挥着重要作用。在心力衰竭中，正面FFR严重钝化甚至变成负面，放松受损，这些是这种疾病的经典标志。因此，进一步了解依赖频率的肌丝过程和修饰对于理解心脏病理生理学至关重要。在这个新兴领域，仍有几个中心问题要解决。钙瞬态和肌丝特性对频率依赖性和动力学的相对贡献是什么？涉及哪些激酶，这些激酶关于FFR的肌丝靶标是什么？基于肌丝的贡献在多大程度上有所不同？导致疾病表型的事件的序列是什么？基于我们以前的工作和当前的初步实验，我们提出了以下假设：基于肌丝的频依赖性调节是通过激酶介导的磷酸化介导的，并且该过程在肥大和心力衰竭中被危险。我们将在两个兔子模型中解决我们的假设，该模型在钙处理和肌丝组成和特性的两个方面表现出非常接近人类的FFR行为，以及通过4个特定目的的非败给和失败的人体组织中的。 力频率关系，2）机械剖析FFR中涉及的基于肌丝的蛋白质靶标和激酶依赖性过程。 3）评估人体心力衰竭组织中频率依赖性激活的变化，以及在肥大的兔模型中，以及4）在新型肌肉培养系统中从健康到心肌失败的过渡期间，FFR的功能和分子变化相关联。总结，这项研究的结果将提供有关心脏患者功能中心缺陷的关键新信息 失败，将使我们能够制定未来的治疗选择。