MECHANISM OF ANESTHETIC PRECONDITIONING

麻醉预处理的机制

• 批准号: 7600719
• 负责人: DAVID C. WARLTIER
• 金额: $ 38.97万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7600719
• 关键词: Address; Anesthesia procedures; Anesthetics; Animals; Attention; Binding; Biochemical; Bioenergetics; Cardiac Myocytes; Cardiovascular Diseases; Cell Death; Collaborations; Communication; Complex; Coronary Arteriosclerosis; Coronary Occlusions; Coupled; Data; Dependence; Electron Transport; Endothelial Cells; Enzymes; Event; Exposure to; Feedback; Funding; Growth Factor; Heat-Shock Proteins 90; Human; Hypoxia; Hypoxia Inducible Factor; In Vitro; Injury; Investigation; Ischemic Preconditioning; Isoflurane; Measurement; Mediating; Mediator of activation protein; Membrane Potentials; Memory; Mitochondria; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Chaperones; Myocardial; Myocardial Ischemia; Nitric Oxide; Nitric Oxide Synthase; Outer Mitochondrial Membrane; Oxidative Phosphorylation; Oxygen measurement, partial pressure, arterial; Pathway interactions; Patients; Permeability; Personal Satisfaction; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Physiological reperfusion; Process; Production; Protein Isoforms; Protein Kinase C; Proteins; Proteome; Proteomics; Rattus; Reactive Oxygen Species; Receptor Protein-Tyrosine Kinases; Regulation; Reperfusion Injury; Reperfusion Therapy; Research; Research Personnel; Risk; Rodent; Role; Signal Transduction; Signal Transduction Pathway; Societies; Structure; Testing; Thinking; Ubiquitination; Vascular Endothelial Growth Factors; Vascular Endothelium; Work; angiogenesis; base; cell type; in vivo; mitochondrial membrane; mouse model; novel therapeutics; preconditioning

The long-term objective of this work is the continued analysis of mechanisms involved in the cardioprotective actions of volatile anesthetics such as isoflurane. Cardioprotection produced by these drugs is well documented across diverse species including rodents, large animals and humans, and mimics ischemic preconditioning in that a prior exposure to the volatile agent continues to be protective after the anesthetic has been eliminated, a phenomenon we termed "anesthetic preconditioning" (ARC). Project I will extend key findings of the previous funding cycle to investigate the global hypothesis that administration of volatile anesthetics such as isoflurane causes a cascade of events including activation of the hypoxia inducible factor la-vascular endothelial growth factor-nitric oxide (HIF1a-VEGF-NO) axis leading to ARC. Specific Aim I will test hypotheses related to how isoflurane regulates myocardial concentrations of HIF1a including actions on intracellular kinases, reactive oxygen species and/or the chaperone protein heat shock protein 90 (HSP90). Enhanced synthesis versus reduced ubiquination mechanisms elicited by isoflurane will be examined. Specific Aim II will test hypotheses related to the contribution of VEGF as an intermediate cardioprotective protein in ARC. Whether VEGF is a mediator of alterations in sarcKATp channel sensitivity and mitochondrial permeability transition by isoflurane will be explored. The importance of vascular endothelium in the protection of cardiomyocytes against hypoxia+reoxygenation injury by isoflurane will be established. Specific Aim III will test hypotheses related to the role and mechanism of action of NO in ARC. The NO synthase (NOS) isoform(s) involved in ARC will be delineated. The effect of NOS inhibition on isoflurane-induced changes in mitochondrial function, mitochondrial proteome, and NO feedback on HIF1a will be determined. NO feedback on HIF1a will be examined as the basis for the memory of ARC. A combination of in vivo rat and mouse models of cardioprotection and in vitro endothelial cell and cardiomyocyte cultures will be used to address the Specific Aims. Molecular and biochemical analyses related to the Specific Aims will be conducted with support from the Molecular and Biochemical and Proteomics Cores. The actions of reactive oxygen species and NO on mitochondrial function and effects of HSP90, an intracellular protein chaperone on the cardioprotection elicited by isoflurane will be studied in collaboration with investigators from Project II and III, respectively. Lay description: Cardiovascular disease is a significant problem in our society, and it is important to define new therapeutic strategies, including optimal delivery of anesthesia to patients with coronary artery disease. Protection against ischemia and reperfusion injury by drugs including the volatile anesthetic isoflurane is a complex process involving multiple intracellular mediators which will be defined by the proposed research.

这项工作的长期目标是对涉及的机制的持续分析 挥发性麻醉药（例如异氟烷）的心脏保护作用。这些药物产生的心脏保护 在包括啮齿动物，大动物和人类在内的各种物种中有充分的文献记载，以及模仿 缺血性预处理，因为事先暴露于挥发性剂后继续保护 消除了麻醉剂，这是我们称为“麻醉预处理”（ARC）的现象。我会的 扩展了先前资金周期的关键发现，以调查全球假设 挥发性麻醉药（例如异氟烷）会导致一系列事件，包括激活缺氧 可诱导因子LA血管内皮生长因子氮（HIF1A-VEGF-NO）轴导致ARC。 具体目的我将测试与异氟醚如何调节心肌浓度HIF1A有关的假设 包括对细胞内激酶，活性氧和/或伴侣蛋白热休克的作用 蛋白质90（HSP90）。增强的合成与降低的泛素化机制将由异氟烷引起 被检查。特定的目标II将检验与VEGF作为中间体的贡献有关的假设 弧中的心脏保护蛋白。 VEGF是否是Sarckatp通道灵敏度改变的中介者 将探索异氟烷的线粒体通透性过渡。血管的重要性 在保护心肌细胞免受缺氧+异氟烷损伤的内皮中，将是 已确立的。特定目标III将检验与NO在ARC中的作用和作用机理有关的假设。 将划定参与ARC的NO合酶（NOS）同工型。 NOS抑制对 异氟烷诱导的线粒体功能，线粒体蛋白质组的变化，而没有对HIF1A的反馈 将确定。没有对HIF1A的反馈作为弧内存的基础。一个 体内大鼠和小鼠心脏保护和体外内皮细胞的组合和 心肌细胞培养物将用于解决特定目的。分子和生化分析 与特定目标相关的将由分子和生化的支持以及 蛋白质组学核心。活性氧的作用以及对线粒体功能的NO的作用和 HSP90，将研究由异氟烷引起的心脏保护上的细胞内蛋白伴侣 分别与项目II和III项目的调查人员合作。 外行描述：心血管疾病是我们社会的重要问题，重要的是 定义新的治疗策略，包括向冠状动脉患者进行麻醉的最佳递送 疾病。保护包括挥发性麻醉的药物免受缺血和再灌注损伤 异氟烷是一个复杂的过程，涉及多个细胞内介质，将由该过程定义 拟议的研究。