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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要心血管疾病（CVD）是全球第一大死亡原因。治疗性进步已经降低了心脏死亡率，但这些治疗和/或干预措施最终增加心力衰竭（HF）的发病率和患病率。高血压、主动脉疾病等疾病心力衰竭中常见的狭窄、容量超负荷和扩张导致腺苷需求长期增加心肌中的三磷酸（ATP）。在心衰缺血条件下，氧化磷酸化的能力 ATP 需求的满足受到损害，对心肌机械功能产生负面影响。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中 TAN 池的减少。缺血性扩张型心肌病 (DCM) 心力衰竭患者样本与年龄匹配的对照组进行比较。引人注目的是，参与嘌呤核苷酸合成、降解和补救途径的酶与心力衰竭的情况，但迄今为止，观察到的心肌嘌呤的原因和后果都还不清楚所描述的失调是很好理解的。我们假设 (1) HF 中出现的 ATP 需求长期升高和/或供应受损的情况条件使心肌嘌呤核苷酸代谢失衡，病理性消耗腺嘌呤核苷酸的心肌； (2) 与腺嘌呤核苷酸相关的代谢变化耗竭会直接影响心脏的机械功能，导致无法满足心脏的需求。心力衰竭时外周血流的需求。在这两个目标中，我们将描述嘌呤代谢如何改变使用生物化学和方法研究衰竭心脏左心室 (LV) 心肌细胞的生物能量学/力学机械评估方法。使用计算建模方法，我们将测试是否病理性嘌呤池耗尽是心力衰竭代谢/能量功能障碍的主要原因（假设 1）并测试是否代谢/能量功能障碍（由于嘌呤代谢失调）导致无法失败心脏以满足周围血流的需求（假设2）。总而言之，我提出的研究是旨在对相关的自然历史、能量和机械功能障碍产生新的见解心肌失代偿和心力衰竭，这可能会产生新的治疗靶点与机械/代谢轴相关。