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（由申请人提供）：冠心病是导致每年超过50万美国公民猝死的原因。心肌缺血后的病理生理学后遗症包括心肌功能低下导致充血性心力衰竭和死亡。缺血后，中性粒细胞既与内皮细胞相互作用，又浸润损伤的心肌。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，导致进一步损伤和氯化产物的产生。我们发现，血浆醇的乙烯基醚键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。缩醛磷脂是心血管系统组织中的主要磷脂亚类。基于活化的中性粒细胞启动氯化脂质家族的积累的发现，以及我们的初步数据表明氯化脂质降低心脏工作，本提案的总体目标是测试新的氯化脂质及其代谢产物是缺血后功能障碍的介质的假设。这一假设将通过两个具体目标进行检验。具体目标1的目的是研究在心肌缺血/再灌注（I/R）过程中体内产生的氯化脂质的不同家族。将在可逆和不可逆的缺血性和正常大鼠损伤的心脏中检查对I/R反应的心肌氯化脂质蓄积的变化。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，该水平将应用于目标2中的离体工作心脏。具体目标2的目的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工作大鼠心脏，以测试其作为心脏收缩功能调节剂的作用，以及使用利用代谢物的稳定同位素和单氯化分子特征的新型质谱筛选测定法来测试其代谢。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，并有可能将氯化脂质代谢物确定为心脏损伤的新生物标志物候选者。了解心肌缺血后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患者护理的见解。由于这是一个基于“高风险”的R21应用，创新性和探索性的性质，这个建议，我们将重点确定在心肌I/R过程中产生的氯化脂质代谢产物的家庭，并确定其对收缩功能障碍的影响。这些氯化脂质代谢产物引起收缩功能障碍的推定机制进行了讨论，作为未来的研究源于本探索性研究。 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是重要的。我们发现了一个新的氯化脂质家族，它们是由中性粒细胞活化产生的。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。