Chlorinated Lipids in Myocardial Ischemia/Reperfusion

氯化脂质在心肌缺血/再灌注中的作用

• 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
• 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

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.

冠心病导致每年超过50万美国公民突然死亡。病情 心肌缺血后的生理后遗症包括抑郁的心肌功能 态度心力衰竭和死亡。局部缺血，中性粒细胞都与内皮相互作用和浸润 jed了心肌。激活的中性粒细胞产生的HOCL可以靶向心脏中存在的生物分子 导致进一步的损伤和产生氯化产品。我们发现 血浆元是中性粒细胞衍生的HOCL的首选靶标，导致2-产生 氯己二烷核和其他几种氯化脂质。血浆元是主要的磷脂 心血管系统组织中的子类。基于激活中性粒细胞引发的发现 氯化脂质家族的积累和我们的初步数据表明氯化脂质 减少心脏工作，该提案的总体目标是检验新型氯化脂质的假设 他们的代谢产物是缺血后功能障碍的介体。该假设将通过两个特定的检验 目标。特定目的1的目标是检查在其中产生的多样化的氯化脂质家族 心肌缺血/再灌注期间的体内（I/R）。心肌氯化的积累的改变 对I/R响应的脂质将在中性粒细胞减少和不可逆地受伤的心脏中检查 正常大鼠。还将评估血浆和尿液中的氯化脂质代谢物以检查其 作为心脏损伤的生物标志物的潜在作用。 AIM 1的结果将建立与生理相关的水平 将应用于AIM 2中的离体工作心脏的氯化脂质。特定目标2的目标是 证明氯化脂质及其代谢产生心脏的生理相关浓度会引起心脏 收缩功能障碍。孤立的工作老鼠心将用稳定的同位素标记的氯化脂质处理 测试他们作为心脏收缩功能调节剂的作用，以及使用新型质量的新陈代谢 利用稳定的同位素和单氯的分子特征的光谱筛选测定 代谢物。拟议的研究具有创新性，因为它们将描绘出后后的新调解人 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 心脏损伤的候选人。了解负责抑郁心脏的生化机制 心肌缺血后的功能代表了美国的主要健康问题。确定新调解人 撞击后缺血功能可能会改善未来患者护理的见解。因为这是R21 基于“高风险”，创新性和探索性的申请，我们将重点介绍 确定心肌I/R期间产生的氯化脂质代谢产物的家族，并确定其影响 关于收缩功能障碍。这些氯化脂质代谢产物的推定机制 该探索性研究引起的未来研究讨论了功能障碍。