Chlorinated Lipids in Myocardial Ischemia/Reperfusion

氯化脂质在心肌缺血/再灌注中的作用

基本信息

批准号：
8403793
负责人：
DAVID A. FORD
金额：
$ 17.85万
依托单位：
SAINT LOUIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-01-01 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8403793
关键词：
Acids Anterior Descending Coronary Artery Archives Biochemical Biological Assay Biological Markers Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Cause of Death Cessation of life Complex Congestive Coronary Artery Ischemia Coronary heart disease Data Depressed mood Endothelial Cells Endothelium Evaluation Family Functional disorder Future Generations Goals Health Heart Heart failure Human Hypochlorous Acid Injury Ischemia Lead Left Lipids Mediating Mediator of activation protein Metabolic Metabolism Modeling Molecular Profiling Myocardial Myocardial Infarction Myocardial Ischemia Myocardium Names Nature Neutrophil Activation Oxidants Patient Care Phospholipids Physiological Plasma Plasmalogens Production Proteins Public Health Rattus Reperfusion Injury Reperfusion Therapy Role Sampling Stable Isotope Labeling Sudden Death Testing Time Tissues Urine Work base high risk improved in vivo in vivo Model injured innovation insight metabolic abnormality assessment neutrophil novel response screening stable isotope stem vinyl ether

项目摘要

Coronary heart disease is responsible for the sudden death of over 500,000 U.S. citizens per year. The patho- physiological sequelae following myocardial ischemia include depressed myocardial function leading to con- gestive heart failure and death. Following ischemia, neutrophils both interact with endothelium and infiltrate in- jured myocardium. Activated neutrophils produce HOCl that can target the biomolecules present in the heart leading to further injury and the generation of chlorinated products. We discovered that the vinyl ether bond of plasmalogens is a preferred target of neutrophil-derived HOCl, resulting in the production of 2- chlorohexadecanal and several other chlorinated lipids. Plasmalogens are a predominant phospholipid subclass in tissues of the cardiovascular system. Based on the discovery that activated neutrophils initiate the accumulation of a family of chlorinated lipids and our preliminary data indicating that chlorinated lipids decrease cardiac work, the overall goal of this proposal is to test the hypothesis that novel chlorinated lipids and their metabolites are mediators of post-ischemic dysfunction. This hypothesis will be tested by two specific aims. The goals of Specific Aim 1 are to examine the diverse family of chlorinated lipids that are produced in vivo during myocardial ischemia/reperfusion (I/R). Alterations in the accumulation of myocardial chlorinated lipids in response to I/R will be examined in reversibly and irreversibly injured hearts from neutropenic and normal rats. Chlorinated lipid metabolites in the plasma and urine will also be assessed to examine their potential role as biomarkers of cardiac injury. Results from Aim 1 will establish physiologically relevant levels of chlorinated lipids that will be applied to ex vivo working hearts in Aim 2. The goals of Specific Aim 2 are to demonstrate that physiologically relevant concentrations of chlorinated lipids and their metabolites elicit cardiac contractile dysfunction. Isolated working rat hearts will be treated with stable isotope-labeled chlorinated lipids to test their role as modulators of cardiac contractile function, as well as their metabolism using a novel mass spectrometric screening assay that exploits both stable isotope and monochlorinated molecular signatures of the metabolites. The proposed studies are innovative because they will delineate new mediators of post- ischemic contractile dysfunction and will potentially identify chlorinated lipid metabolites as new biomarker candidates of cardiac injury. Understanding the biochemical mechanisms responsible for depressed cardiac function following myocardial ischemia represents a major U.S. health concern. Identifying new mediators that impact post-ischemic function may lead to improved insights for patient care in the future. Since this is an R21 application based on the "high risk", innovative and exploratory nature of this proposal, we will focus on identifying the family of chlorinated lipid metabolites produced during myocardial I/R, and identify their impact on contractile dysfunction. Putative mechanisms by which these chlorinated lipid metabolites elicit contractile dysfunction are discussed as future studies stemming from this exploratory study.

冠心病每年导致超过 50 万美国公民猝死。悲怆—— 心肌缺血后的生理后遗症包括导致心肌功能下降妊娠性心力衰竭和死亡。缺血后，中性粒细胞与内皮相互作用并浸润损伤心肌。激活的中性粒细胞产生 HOCl，可以靶向心脏中存在的生物分子导致进一步的伤害和氯化产物的产生。我们发现乙烯基醚键缩醛磷脂是中性粒细胞衍生的 HOCl 的首选目标，导致产生 2- 氯十六醛和其他几种氯化脂质。缩醛磷脂是主要的磷脂心血管系统组织中的亚类。基于激活的中性粒细胞启动的发现氯化脂质家族的积累以及我们的初步数据表明氯化脂质减少心脏做功，该提案的总体目标是检验新型氯化脂质的假设它们的代谢物是缺血后功能障碍的介质。这个假设将通过两个特定的目标。具体目标 1 的目标是检查在以下环境中产生的不同氯化脂质家族：心肌缺血/再灌注（I/R）期间的体内。心肌氯化积累的变化将在因中性粒细胞减少症和中性粒细胞减少症而导致可逆性和不可逆性损伤的心脏中检查对 I/R 反应的脂质。正常老鼠。血浆和尿液中的氯化脂质代谢物也将被评估以检查其作为心脏损伤生物标志物的潜在作用。目标 1 的结果将建立生理相关水平氯化脂质将应用于目标 2 中的离体工作心脏。具体目标 2 的目标是证明氯化脂质及其代谢物的生理相关浓度会引起心脏收缩功能障碍。将用稳定同位素标记的氯化脂质处理离体的工作大鼠心脏使用新型质量测试它们作为心脏收缩功能调节剂的作用以及它们的新陈代谢利用稳定同位素和一氯化分子特征的光谱筛选分析代谢物。拟议的研究具有创新性，因为它们将描绘出新的后调解因素。缺血性收缩功能障碍，并有可能将氯化脂质代谢物识别为新的生物标志物心脏损伤的候选者。了解导致心脏抑制的生化机制心肌缺血后的功能是美国的一个主要健康问题。确定新的调解者缺血后功能的影响可能会改善未来患者护理的见解。因为这是R21 基于本提案的“高风险”、创新性和探索性应用，我们将重点关注鉴定心肌缺血再灌注期间产生的氯化脂质代谢物家族，并确定其影响关于收缩功能障碍。这些氯化脂质代谢物引起收缩的假定机制功能障碍将作为这项探索性研究的未来研究进行讨论。