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: 10593961
• 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/10593961
• 关键词: 12-HETE; Ablation; Address; Arachidonate 12-Lipoxygenase; Arachidonate 15-Lipoxygenase; Attenuated; Binding; 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; Derivation procedure; 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; Incubated; Industrialization; Inflammation; Inflammation Mediators; Inflammatory; Iron; Iron Chelation; Ketone Bodies; Knowledge; Label; Ligands; Lipid Peroxides; Lipids; Lysophosphatidylcholines; Lysophospholipids; Macrophage; Mediating; Membrane; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Molecular; Myocardial Ischemia; Myocardium; NADP; Oxidases; Oxidation-Reduction; Oxidative Stress; 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; 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最常见的死亡原因。在我们的学习过程中， 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，这些途径导致 2-花生四烯酰-溶血磷脂酰胆碱（2-AA-LPC）和2-花生四烯酰-的生成 溶血磷脂酰乙醇胺（2-AA-LPE）。其中包括：1) iPLA2g (PNPLA8) 被鉴定为 具有 sn-1 特异性的磷脂酶； 2) 氧化心磷脂激活的细胞色素 c 作为缩醛磷脂酶 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 cyclooxygenase-2 的极好底物，可产生大量意想不到的代谢物。值得注意的是， 这些底物与 12-脂氧合酶或 15-脂氧合酶一起孵育，导致其氧化为 12- H(p)ETE-或15-H(p)ETE-溶血磷脂。基于这些发现，我们鉴定了 2-AA-LPC 和 2-AA-LPE 作为脂质合成和人类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 确定了人类心脏线粒体衰竭时产生更多 HETE 类二十烷酸的能力 与非失败对照线粒体相比，对 Ca2+ 挑战的反应。最近，铁死亡被 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。心肌梗塞时 缺血和心力衰竭时，很大一部分线粒体铁 (Fe+3) 从其结合状态释放，变成 游离 Fe+2 通过 Haber-Weiss 和 Fenton 型引发活性氧 (ROS) 的形成 化学。本研究旨在确定负责的重要机制的作用 氧化脂质及其在衰竭心肌膜功能障碍中的作用。拟议的研究将集中于 从机械上理解导致人类衰竭心脏中氧化脂质产生的机制。 具体来说，我们将鉴定不同类别的氧化脂质中的手性富集，以深入了解 心力衰竭治疗的未来转化目标。如果脂质氧化主要是酶介导的，那么特定的 可以在拟议的研究中确定目标酶。或者，如果脂质氧化很大程度上 由非酶 Fe+2 机制介导/引发，然后是 Fe 螯合方法和膜内自由基 可以探索陷阱。在具体目标 3 中，我们将研究氧化脂质在不同细胞活化中的作用 来自女性和男性受试者的控制和心脏衰竭的类型。炎症对心脏的重要性 疾病现已得到充分记录，但氧化脂质在激活免疫系统不同细胞中所起的作用 仍处于最初的理解阶段。为了跨越我们知识上的这一差距，我们将研究以下因素的影响： 心血管系统中选定细胞（例如心肌细胞、成纤维细胞、内皮细胞）上的不同氧化脂质 细胞和巨噬细胞）。通过了解氧化脂质有害影响的机制 根据人类心脏的线粒体功能，可以采用多层次的方法治疗充血性心力衰竭 实现了靶向酶介导的氧化、Fe2+介导的氧化和自由基传播终止剂。