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.

项目总结