Causes and consequences of myocardial purine dysregulation in heart failure

心力衰竭心肌嘌呤失调的原因和后果

• 批准号: 10227249
• 负责人: Edith Jones
• 金额: $ 3.8万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-10 至 2022-08-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10227249
• 关键词: Actins; Adenine Nucleotides; Adenosine Triphosphate; Age; Agreement; Animal Model; Aortic Valve Stenosis; Biochemical; Biochemistry; Bioenergetics; Biological Assay; Biological Models; Blood flow; Calcium; Carbohydrates; Cardiac; Cardiac Catheterization Procedures; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Chemicals; Chronic; Citric Acid Cycle; Computer Models; Coupling; Data; Defect; Dilated Cardiomyopathy; Echocardiography; Energy Supply; Enzymes; Etiology; Fatty Acids; Functional disorder; Goals; Heart; Heart Research; Heart failure; Human; Hydrolysis; Hypertension; Impairment; Incidence; Individual; Intervention; Kinetics; Lead; Left; Link; Measures; Mechanics; Metabolic; Metabolism; Mitochondria; Modeling; Muscle Cells; Myocardial; Myocardial tissue; Myocardium; Myosin ATPase; Natural History; Ohio; Output; Oxidative Phosphorylation; Oxygen; Pathologic; Pathway interactions; Patients; Performance; Phenotype; Play; Prevalence; Purine Nucleotides; Purines; Role; Sampling; Sum; Testing; Therapeutic; Tissues; Ventricular; assay development; base; design; experimental study; heart function; human model; improved; inorganic phosphate; insight; mechanical load; metabolic phenotype; mortality; multi-scale modeling; new therapeutic target; nucleotide metabolism; oxidation; purine metabolism; sex

Project Summary Cardiovascular diseases (CVDs) represent the number one cause of death worldwide. Therapeutic advancements have improved cardiac mortality rates yet these treatments and/or interventions have ultimately increased the incidence and prevalence of Heart Failure (HF). Conditions such as hypertension, aortic stenosis, volume overload, and dilation often present in HF lead to chronically increased demand of adenosine triphosphate (ATP) in myocardium. During ischemic conditions in HF the ability of oxidative phosphorylation to meet the demand for ATP is impaired with negative implications in myocardial mechanical function. In agreement with other studies in animal models of HF, a depletion of the Total Adenine nucleotide (TAN) has been observed by our lab, and we have likewise observed a decrease in the TAN pool in ischemic and non- ischemic Dilated Cardiomyopathy (DCM) HF patient samples compared to age matched controls. Strikingly, enzymes involved in purine nucleotide synthesis, degradation, and salvage pathways have been implicated in HF conditions, yet to this day neither the causes nor the consequences of the observed myocardial purine dysregulation described are well understood. We hypothesize that (1) Conditions of chronically elevated ATP demand and/or impair supply that occur in HF conditions dispose the myocardium to an imbalance in purine nucleotide metabolism pathologically depleting the myocardium of adenine nucleotides; and (2) Metabolic changes associated with adenine nucleotide depletion have a direct impact on the mechanical function of the heart, contributing to the inability to meet the blood-flow demands of the periphery in HF. In the two aims, we will characterize how purine metabolism alters bioenergetics/mechanics in the left ventricular (LV) cardiomyocyte of the failing heart using biochemistry and mechanic assessment approaches. Using computational modeling approaches, we will test if pathological depletion of purine pools is a primary cause of metabolic/energetic dysfunction in HF (Hypothesis 1) and test if metabolic/energetic dysfunction (due to purine metabolism dysregulation) contributes to the inability of failing heart to meet the blood-flow demands of the periphery (Hypothesis 2). In sum, my proposed studies are designed to yield new insights into the linked natural history, energetic and mechanical dysfunction of the myocardium in cardiac decompensation and heart failure, which could potentially yield new therapeutic targets associated with the mechanical/metabolic axis.

项目摘要 心血管疾病（CVD）是全球头号死亡原因。治疗 这些进展已经改善了心脏病死亡率，但这些治疗和/或干预最终 增加了心力衰竭（HF）的发病率和患病率。高血压、主动脉 HF中经常出现的狭窄、容量超负荷和扩张导致对腺苷的需求慢性增加 三磷酸（ATP）。在HF缺血状态下，氧化磷酸化的能力， 满足ATP的需求受损，对心肌机械功能有负面影响。在 与HF动物模型中的其他研究一致，总腺嘌呤核苷酸（TAN）的消耗 我们的实验室观察到，我们同样观察到缺血性和非缺血性的TAN池减少。 缺血性扩张型心肌病（DCM）HF患者样品与年龄匹配的对照相比。引人注目的是， 参与嘌呤核苷酸合成、降解和补救途径的酶已经涉及到 HF条件下，但到今天，无论是原因还是观察到的心肌嘌呤的后果， 所描述的失调是很好理解的。 我们假设：（1）HF患者ATP需求长期升高和/或供应受损， 条件使心肌处于嘌呤核苷酸代谢的不平衡，病理性消耗 腺嘌呤核苷酸对心肌的影响;（2）腺嘌呤核苷酸相关的代谢变化 消耗对心脏的机械功能有直接影响，导致无法满足 HF中外周的血流需求。在这两个目标中，我们将描述嘌呤代谢如何改变 在衰竭心脏的左心室（LV）心肌细胞中使用生物化学和 机械评价方法。使用计算建模方法，我们将测试是否病理性 嘌呤池的耗竭是HF中代谢/能量功能障碍的主要原因（假设1），并测试 代谢/能量功能障碍（由于嘌呤代谢失调）导致不能进行 以满足外周的血流需求（假设2）。总而言之，我建议的研究是 旨在产生新的见解联系的自然历史，精力充沛和机械功能障碍的 心脏失代偿和心力衰竭中的心肌，这可能会产生新的治疗靶点 与机械/代谢轴相关。