Novel Lipid 2nd Messengers Regulating Bioenergetics and Signaling in Human Myocardium

调节人体心肌生物能和信号传导的新型脂质第二信使

• 批准号: 10378709
• 负责人: RICHARD W GROSS
• 金额: $ 58.12万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10378709
• 关键词: 12-HETE; Address; Arachidonate 12-Lipoxygenase; Arachidonate 15-Lipoxygenase; Attenuated; Bioenergetics; CRISPR/Cas technology; Cardiac; Cardiac Myocytes; Cardiolipins; Cardiovascular Diseases; Cardiovascular system; Carnitine; Cause of Death; Cell Death; Cells; Chemicals; Chemistry; Citric Acid Cycle; Complex; Congestive Heart Failure; Developed Countries; Eicosanoids; Endothelial Cells; Environment; Enzymes; Female; Fibroblasts; Free Radicals; Functional disorder; Future; G-Protein-Coupled Receptors; Generations; Glutathione Disulfide; Grant; Heart; Heart Diseases; Heart Mitochondria; Heart failure; Human; Hydrolysis; Hydroxyeicosatetraenoic Acids; Immune system; Industrialization; Inflammation; Inflammation Mediators; Inflammatory; Iron; Iron Chelation; Ketone Bodies; Knowledge; Label; Lead; Ligands; Lipid Peroxides; Lipids; Lipoxygenase; Lysophosphatidylcholines; Lysophospholipids; Mediating; Membrane; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Molecular; Myocardial Ischemia; Myocardium; NADP; Oxidases; Oxidation-Reduction; Oxidative Stress; Oxides; Palmitates; Parents; Pathway interactions; Phospholipases A; Phospholipids; Plasmalogens; Play; Predisposition; Production; Proteins; Publishing; Pyruvate; Reaction; Reactive Oxygen Species; Research; Resolution; Respiration; Role; Signal Transduction; Societies; Specificity; Stress; Substrate Cycling; Succinates; Technology; Ubiquinone; beta-Hydroxybutyrate; cell type; cellular targeting; chemoproteomics; cyclooxygenase 2; cytochrome c; cytokine; diagnostic signature; experimental study; inhibitor; insight; interest; lipid mediator; lipid metabolism; lipidome; macrophage; male; monocyte; novel; oxidation; oxidized lipid; polyunsaturated fat; protein complex; receptor; research study; response; stable isotope; targeted treatment; ubiquinol

ABSTRACT Cardiovascular disease is the most common cause of death in industrialized nations. During the course of our studies, we have identified previously undiscovered mitochondrial pathways of lipid metabolism and signaling which lead to the generation of 2-arachidonoyl-lysophosphatidylcholine (2-AA-LPC) and 2-arachidonoyl- lysophosphatidylethanolamine (2-AA-LPE). These include: 1) the identification of iPLA2g (PNPLA8) as a phospholipase with sn-1 specificity; and 2) oxidized cardiolipin-activated cytochrome c serving as a plasmalogenase catalyzing the production of 2-AA LPC and 2-AA LPE. Further research demonstrated that 2-AA-LPC and 2-AA-LPE are excellent substrates for cyclooxygenase-2 resulting in a plethora of unanticipated metabolites. Remarkably, incubation of these substrates with either 12-lipoxygenase or 15-lipoxygenase resulted in their oxidation to 12- H(p)ETE- or 15-H(p)ETE-lysophospholipids. Building upon these discoveries we identified 2-AA-LPC and 2-AA-LPE as signaling and metabolic nodes in lipid synthesis and human heart mitochondrial function. Importantly, we have identified the ability of failing human heart mitochondria to generate increased amounts of HETE eicosanoids in response to Ca2+ challenge in comparison to non-failing control mitochondria. Recently, ferroptosis has been identified as a mechanism that leads to cell death through the accumulation of lipid hydroperoxides. During myocardial ischemia and heart failure, a substantial portion of mitochondrial iron (Fe+3) is released from its bound state to become free Fe+2 that initiates the formation of reactive oxygen species (ROS) through Haber-Weiss and Fenton-type chemistries. The present research is targeted to identifying the roles of prominent mechanisms responsible for the oxidized lipids and their roles in membrane dysfunction in failing myocardium. The proposed research will focus on mechanistically understanding the mechanisms leading to oxidized lipid production in the failing human heart. Specifically, we will identify the chiral enrichment in different classes of oxidized lipids to gain mechanistic insight into future translational targets for therapy of heart failure. If lipid oxidation is largely enzyme-mediated, then specific enzymes can be targeted that will be identified in the proposed research. Alternatively, if lipid oxidation is largely mediated/initiated by non-enzymatic Fe+2 mechanisms then Fe chelation approaches and intramembrane radical traps can be explored. In Specific Aim 3, we will investigate the roles of oxidized lipids in the activation of different cell types from control and from failing hearts from female and male subjects. The importance of inflammation in heart disease is now well documented, but the roles oxidized lipids play in activating different cells of the immune system is still at its earliest stages of understanding. To traverse this gap in our knowledge, we will examine the effects of different oxidized lipids on selected cells in the cardiovascular system (e.g., cardiac myocytes, fibroblasts, endothelial cells, and macrophages). Through understanding the mechanisms underlying the deleterious effects of oxidized lipids on mitochondrial function in human hearts, a multi-tiered approach for treatment of congestive heart failure can be realized targeting enzyme-mediated oxidation, Fe2+ mediated oxidation and terminators of free radical propagation.

抽象的 心血管疾病是工业化国家中最常见的死亡原因。在学习过程中， 我们已经确定了以前未被发现的脂质代谢和信号传导的线粒体途径 生成2-芳己烯酰基溶质磷脂酰胆碱（2-AA-LPC）和2-芳基二烯酰基 - 溶血磷脂酰乙醇胺（2-AA-LPE）。其中包括：1）IPLA2G（PNPLA8）的识别为 具有SN-1特异性的磷脂酶； 2）用作血浆基因酶的氧化的心磷脂激活的细胞色素C 催化2-AA LPC和2-AA LPE的生产。进一步的研究表明，2-AA-LPC和2-AA-LPE 是环氧酶-2的优秀底物，导致大量意外的代谢产物。值得注意的是 将这些底物与12-氯氧合酶或15-脂氧合酶一起孵育，从而导致其氧化至12-- H（p）Ete-或15-h（p）Ete-散脂磷脂。在这些发现的基础上，我们确定了2-AA-LPC和2-AA-LPE 作为脂质合成和人心脏线粒体功能中的信号传导和代谢节点。重要的是，我们有 确定了失败的人类心脏线粒体产生增加量增加的heete eicosanoids的能力 与非损耗控制线粒体相比，对CA2+挑战的反应。最近，铁铁病已经 被确定为通过脂质氢过氧化物的积累导致细胞死亡的机制。在心肌期间 缺血和心力衰竭，线粒体铁的很大一部分（Fe+3）从其结合状态释放为 Fe+2通过Haber-Weiss和Fenton型启动活性氧（ROS）的形成 化学。本研究的目的是确定负责该的突出机制的作用 氧化的脂质及其在膜功能障碍中的作用在心肌失败中。拟议的研究将重点 机械学理解导致失败的人心中氧化脂质产生的机制。 具体而言，我们将确定不同类别的氧化脂质中的手性富集，以获得机械洞察力的洞察力 心力衰竭治疗的未来翻译目标。如果脂质氧化在很大程度上是酶介导的，则 可以在拟议的研究中鉴定的酶。或者，如果脂质氧化很大 通过非酶Fe+2的机制介导/引发，然后Fe螯合接近和膜内自由基 可以探索陷阱。在特定目标3中，我们将研究氧化脂质在不同细胞激活中的作用 来自控制的类型以及女性和男性受试者的心脏失败。心脏炎症的重要性 疾病现在已经有充分的文献记载，但是氧化脂质的作用在激活免疫系统的不同细胞中起着作用 仍处于其最早的理解阶段。在我们的知识上，我们将研究这一差距 心血管系统中选定细胞的不同氧化脂质（例如心肌细胞，成纤维细胞，内皮 细胞和巨噬细胞）。通过了解氧化脂质的有害作用的基础机制 关于人心中的线粒体功能，一种多层治疗充血性心力衰竭的方法可以是 实现靶向酶介导的氧化，Fe2+介导的氧化和自由基繁殖的终止剂。