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.

冠心病是造成每年超过50万美国公民猝死的原因。可怜的- 心肌缺血后的生理学后遗症包括心肌功能降低， 胃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，并浸润到- 心肌损伤活化的中性粒细胞产生HOCl，其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 缩醛磷脂是嗜水气单胞菌衍生的HOCl的优选靶标，导致产生2- 氯代十六烷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 一个氯化脂质家族的积累，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的氯化脂质 并且它们的代谢物是缺血后功能障碍的介质。这一假设将由两个具体的 目标。具体目标1的目标是检查在体内产生的氯化脂质的不同家族。 在体内心肌缺血/再灌注（I/R）期间。心肌氯化物积累的变化 脂质对I/R的反应将在可逆性和不可逆性损伤的心脏中进行检查， 正常老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。目标1的结果将建立生理相关水平的 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 表明生理相关浓度的氯化脂质及其代谢物引起心脏 收缩功能障碍将用稳定同位素标记的氯化脂质处理离体工作大鼠心脏 为了测试它们作为心脏收缩功能调节剂的作用，以及使用新的质量来测试它们的代谢， 光谱筛选分析，利用稳定同位素和单氯化分子签名， 代谢物。拟议的研究是创新的，因为它们将描绘新的调解人后， 缺血性收缩功能障碍，并将有可能确定氯化脂质代谢物作为新的生物标志物 心脏损伤的候选人。了解抑郁性心脏病的生化机制 心肌缺血后的功能是美国主要的健康问题。确定新的调解人， 缺血后功能的影响可能会导致未来患者护理的改善。因为这是R21 基于应用的“高风险”、创新性和探索性，本提案将重点 确定心肌I/R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 功能障碍的讨论，作为未来的研究源于这项探索性研究。