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：
8227162
负责人：
DAVID A. FORD
金额：
$ 22.5万
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/8227162
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 Heart Failure Coronary Artery Ischemia Coronary heart disease Data Depressed mood Endothelial Cells Endothelium Evaluation Family Functional disorder Future Generations Goals Health Heart 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 Plasma Plasmalogens Production Proteins Public Health Rattus Reperfusion Injury Reperfusion Therapy Role Sampling Screening procedure 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 stable isotope stem vinyl ether

项目摘要

DESCRIPTION (provided by applicant): Coronary heart disease is responsible for the sudden death of over 500,000 U.S. citizens per year. The pathophysiological sequelae following myocardial ischemia include depressed myocardial function leading to congestive 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. PUBLIC HEALTH RELEVANCE: Elucidating the mechanisms that chlorinated lipids mediate the pathophysiological sequelae of myocardial ischemia/reperfusion is important from a U.S. public health perspective. We have discovered a new family of chlorinated lipids that are produced as a result of neutrophil activation. The role of these chlorinated lipids in post-ischemic contractile dysfunction will be examined in the proposed studies.

描述（由申请人提供）：每年有超过 500,000 名美国公民因冠心病猝死。心肌缺血后的病理生理学后遗症包括心肌功能下降，导致充血性心力衰竭和死亡。缺血后，中性粒细胞与内皮细胞相互作用并浸润受损的心肌。活化的中性粒细胞产生 HOCl，它可以靶向心脏中存在的生物分子，导致进一步损伤并产生氯化产物。我们发现缩醛磷脂的乙烯基醚键是中性粒细胞衍生的 HOCl 的首选目标，导致 2-氯十六醛和其他几种氯化脂质的产生。缩醛磷脂是心血管系统组织中主要的磷脂亚类。基于活化的中性粒细胞启动氯化脂质家族积累的发现以及我们的初步数据表明氯化脂质会减少心脏做功，该提案的总体目标是检验新的氯化脂质及其代谢物是后应激介质的假设。 -缺血性功能障碍。这一假设将通过两个具体目标进行检验。具体目标 1 的目标是检查心肌缺血/再灌注 (I/R) 期间体内产生的不同氯化脂质家族。将在中性粒细胞减少症和正常大鼠的可逆性和不可逆性损伤的心脏中检查心肌氯化脂质积累对I/R的反应的变化。血浆和尿液中的氯化脂质代谢物也将被评估，以检查它们作为心脏损伤生物标志物的潜在作用。目标 1 的结果将确定氯化脂质的生理相关水平，并将其应用于目标 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，以测试它们作为心脏收缩功能调节剂的作用，以及使用新型质谱筛选测定法测试它们的代谢，该测定法利用代谢物的稳定同位素和一氯化分子特征。拟议的研究具有创新性，因为它们将描述缺血后收缩功能障碍的新介质，并有可能将氯化脂质代谢物识别为心脏损伤的新生物标志物候选物。了解心肌缺血后导致心脏功能下降的生化机制是美国的一个主要健康问题。识别影响缺血后功能的新介质可能会改善未来对患者护理的见解。由于这是基于该提案的“高风险”、创新性和探索性的 R21 申请，因此我们将重点鉴定心肌 I/R 期间产生的氯化脂质代谢物家族，并确定它们对收缩功能障碍的影响。这些氯化脂质代谢物引起收缩功能障碍的假定机制将作为本探索性研究的未来研究进行讨论。公共卫生相关性：从美国公共卫生的角度来看，阐明氯化脂质介导心肌缺血/再灌注的病理生理学后遗症的机制非常重要。我们发现了一个新的氯化脂质家族，它们是中性粒细胞激活的结果。这些氯化脂质在缺血后收缩功能障碍中的作用将在拟议的研究中进行检查。