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持续分析涉及的机制 异氟烷等挥发性麻醉剂的心脏保护作用。这些药物产生的心脏保护作用 在包括啮齿类动物、大型动物和人类以及模仿者在内的不同物种中都有详细记录 缺血预适应，即之前暴露于挥发性物质在缺血后仍然具有保护作用 麻醉剂已被消除，这种现象我们称为“麻醉预处理”（ARC）。项目我会 扩展上一个资助周期的主要发现，以调查以下全球假设： 异氟烷等挥发性麻醉剂会引起一系列事件，包括激活缺氧 诱导因子la-血管内皮生长因子-一氧化氮（HIF1a-VEGF-NO）轴导致ARC。 具体目标 我将测试与异氟烷如何调节心肌 HIF1a 浓度相关的假设 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)。异氟烷引起的增强合成与减少泛素化机制将 被检查。具体目标 II 将测试与 VEGF 作为中间体的贡献相关的假设 ARC 中的心脏保护蛋白。 VEGF 是否是 sarcKATp 通道敏感性改变的介质 并将探讨异氟烷对线粒体通透性的转变。血管的重要性 内皮细胞保护心肌细胞免受异氟醚缺氧+复氧损伤的作用 已确立的。具体目标 III 将检验与 NO 在 ARC 中的作用和作用机制相关的假设。 将描述参与 ARC 的一氧化氮合酶 (NOS) 同工型。 NOS抑制作用 异氟烷诱导的线粒体功能、线粒体蛋白质组和 HIF1a 上的 NO 反馈变化 将被确定。不会检查 HIF1a 的反馈作为 ARC 记忆的基础。一个 体内大鼠和小鼠心脏保护模型与体外内皮细胞的组合 心肌细胞培养物将用于实现特定目标。分子和生化分析 与具体目标相关的研究将在分子和生物化学和 蛋白质组学核心。活性氧和NO对线粒体功能的作用及其影响 HSP90，一种细胞内蛋白伴侣，对异氟烷引起的心脏保护作用将在 分别与项目 II 和 III 的研究人员合作。 外行描述：心血管疾病是我们社会的一个重大问题，重要的是 确定新的治疗策略，包括为冠状动脉患者提供最佳麻醉 疾病。通过药物（包括挥发性麻醉剂）预防缺血和再灌注损伤 异氟烷是一个涉及多种细胞内介质的复杂过程，其定义为 提出的研究。