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: 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
• 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

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(申请人提供)：每年有50多万美国公民因冠心病猝死。心肌缺血后的病理生理后遗症包括心脏功能低下，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，并渗入受损心肌。激活的中性粒细胞产生HOCl，它可以靶向心脏中存在的生物分子，导致进一步的损伤和氯化产物的产生。我们发现，血浆原的乙烯基醚键是中性粒细胞来源的HOCl的首选靶标，导致2-氯十六醛和其他几种氯化脂质的产生。血浆原是心血管系统组织中的一个主要磷脂亚类。基于激活的中性粒细胞启动一系列氯化脂质积累的发现，以及我们的初步数据表明氯化脂质减少心脏做功，这一提议的总体目标是检验新的氯化脂质及其代谢物是缺血后功能障碍的介体的假设。这一假设将通过两个具体目标进行检验。具体目标1的目标是检测在心肌缺血/再灌注(I/R)期间体内产生的各种氯化脂质家族。在中性粒细胞减少和正常大鼠的可逆性和不可逆性损伤的心脏中，将检测对I/R反应的心肌氯化脂质积累的变化。还将评估血浆和尿液中的氯化脂质代谢物，以检查它们作为心脏损伤生物标记物的潜在作用。目标1的结果将确定生理上相关的氯化脂质水平，这些水平将应用于目标2中的体外工作心脏。特定目标2的目标是证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。分离的工作大鼠心脏将被稳定同位素标记的氯化脂质处理，以测试它们作为心脏收缩功能调节器的作用，以及使用一种利用代谢物的稳定同位素和一氯化分子特征的新型质谱学筛选方法来测试它们的新陈代谢。拟议的研究具有创新性，因为它们将描绘缺血后收缩功能障碍的新介质，并可能将氯化脂质代谢产物确定为心脏损伤的新生物标记物候选。了解导致心肌缺血后心功能下降的生化机制是美国的一个主要健康问题。确定影响缺血后功能的新介质可能会改善未来患者护理的洞察力。由于这是一项基于该提议的“高风险”、创新性和探索性的R21应用，我们将重点确定在心肌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可能机制将作为这项探索性研究的后续研究进行讨论。 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/再灌注的病理生理后遗症的机制是重要的。我们发现了一种新的氯化脂质家族，它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验。