Chlorinated Lipids in Myocardial Ischemia/Reperfusion

每年有50多万美国人死于冠心病。可悲的是- 心肌缺血后的生理后遗症包括心肌功能低下，导致心肌梗死。 消化性心力衰竭和死亡。缺血后，中性粒细胞与血管内皮细胞相互作用，并渗入血管内皮细胞。 受损的心肌。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 导致进一步的伤害和氯化产品的产生。我们发现分子中的乙烯基醚键 血浆原是中性粒细胞来源的HOCl的首选靶标，导致2- 氯代十六烷醛和其他几种氯化脂。血浆原是一种主要的磷脂 心血管系统组织中的一个亚纲。基于这一发现，激活的中性粒细胞启动 一类氯化脂质的积累和我们的初步数据表明，氯化脂质 减少心脏做功，这项提议的总体目标是测试新的氯化脂质的假设 它们的代谢产物是缺血后功能障碍的介体。这一假设将通过两个具体的 目标。具体目标1的目标是检查在体内产生的各种氯化脂质家族 活体心肌缺血/再灌流(I/R)。心肌氯离子蓄积的变化 对I/R反应的脂质将在中性粒细胞减少和不可逆损伤的心脏中检测 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 作为心脏损伤生物标志物的潜在作用。目标1的结果将建立生理上相关的水平 将在目标2中应用于体外工作心脏的氯化脂质。具体目标2的目标是 证明生理上相关浓度的氯化脂质及其代谢物可诱导心脏 收缩功能障碍。分离的工作大鼠心脏将用稳定同位素标记的氯化脂质治疗 使用一种新的物质来测试它们作为心脏收缩功能调节器的作用，以及它们的新陈代谢 光谱筛选分析同时利用稳定的同位素和一氯化的分子特征 代谢物。拟议的研究具有创新性，因为它们将描绘出新的后调解因素。 缺血性收缩功能障碍和可能将氯化脂质代谢产物确定为新的生物标记物 心脏损伤的候选人。了解导致心脏压抑的生化机制 心肌缺血后的功能是美国的一个主要健康问题。确定新的调解人 对缺血后功能的影响可能会改善对未来患者护理的洞察力。因为这是一辆R21 基于这一建议的高风险性、创新性和探索性，我们将重点研究 鉴定心肌I/R期间产生的氯化脂质代谢物家族，并鉴定其影响 关于收缩功能障碍。这些氯化类脂代谢物引起收缩的可能机制 在此探索性研究的基础上，对功能障碍的未来研究进行了讨论。

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.