Mechanisms of Hypothermic Protection from Ischemia/Reperfusion Cardiac Injury

低温保护缺血/再灌注心脏损伤的机制

• 批准号: 7885246
• 负责人: KIMM J HAMANN
• 金额: $ 38.38万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7885246
• 关键词: Achievement; Acute; Adult; Affect; Animal Model; Animals; Antioxidants; Apoptosis; Apoptotic; Attenuated; Blood Circulation; Cardiac; Cardiac Myocytes; Cardiovascular system; Caspase; Cell model; Cells; Cessation of life; Cytoplasm; Data; Dose; Down-Regulation; Family; Functional disorder; Generations; Genes; Genetic; Genetic Transcription; Goals; Heart Arrest; Hour; In Vitro; Injury; Ischemia; Knock-out; Knockout Mice; Laboratories; Location; Matrix Metalloproteinases; Mediating; Membrane Potentials; Messenger RNA; Meta-Analysis; Mitochondria; Mitochondrial Proteins; Modeling; Molecular; Molecular Profiling; Mus; Mutant Strains Mice; Myocardial; Myocardial Ischemia; Myocardial dysfunction; Myocardium; NOS3 gene; Nitric Oxide; Nitric Oxide Signaling Pathway; Oxidants; Pathway interactions; Patients; Phenotype; Preparation; Production; Protein Family; Proteins; Protocols documentation; Reaction; Reactive Nitrogen Species; Reactive Oxygen Species; Recovery; Reperfusion Injury; Reperfusion Therapy; Research Personnel; Resuscitation; Role; Serum; Signal Pathway; Signal Transduction; Small Interfering RNA; Source; Stress; Superoxides; TP53 gene; Techniques; Testing; Therapeutic; Tissues; Translating; Work; antioxidant therapy; cytochrome c; hemodynamics; improved; in vivo; induced hypothermia; member; mitochondrial membrane; mortality; mouse model; natural hypothermia; oxidant stress; prevent; protective effect; response

DESCRIPTION (provided by applicant): Therapeutic hypothermia can significantly attenuate post-resuscitation injury and improve survival in some patients. In our cellular and animal models of global ischemia, there is significant post-resuscitation cardiac injury. The central hypothesis of this proposal is that hypothermia initiated during ischemia protects cardiomyocytes and preserves cardiac function through interrelated pathways, involving the production of nitric oxide (NO) and p53 down-regulation, which act at the mitochondria to prevent initiation of the apoptotic cascade. Using a combination of established normothermic and hypothermic cellular and animal models, we propose two major specific aims: 1) Determine the interacting roles of hypothermia-induced nitric oxide, modulation of reactive oxygen species (ROS) and the mitochondrion in protecting cardiomyocytes and the heart from ischemia/reperfusion (l/R)-induced injury. We hypothesize that intra-ischemic hypothermic protection involves the generation of an altered ROS and reactive nitrogen species (RNS) profile, allowing recovery of ischemia-reduced mitochondrial membrane potential and blocking the release of cytochrome c (cyt c) from the mitochondria. In these studies, we will examine the induction or modulation of specific oxidants, such as superoxide and nitric oxide, by hypothermia and these effects on the initiation of the mitochondrial pathway of apoptosis. 2) Determine the interactions between mitochondrial Bcl-2 family proteins, specifically Bax and Bak, and other "mitochondria-targeted" proteins, specifically p53, through which hypothermia-induced NO generation provides protection and prevents release of pro-apoptotic mitochondrial proteins cyt c and activation of caspases. We hypothesize that activation of p53 during I/R leads to activation of Bax and/or Bak and hypothermic blockade of p53 activation, interactions with Bax/Bak, and/or translocation will inhibit these interactions, blocking the release of cyt c and protecting the cells from apoptosis. The proposed studies will elucidate the molecular mechanisms involved in the hypothermic induction of protection of cardiomyocytes, including details of the "adaptive" or protective hypothermic oxidant profile. An understanding of mechanisms by which specific mitochondrial pathways of apoptosis are affected by hypothermic signaling will aid in developing optimal protective protocols in hypothermic, pharmacological and genetic therapeutic approaches.

描述（由申请人提供）：治疗性低温可以显著减轻复苏后损伤，并提高某些患者的生存率。在我们的全脑缺血的细胞和动物模型中，存在显著的复苏后心脏损伤。这一建议的中心假设是，在缺血期间开始的低温保护心肌细胞，并通过相关的途径，包括一氧化氮（NO）和p53下调，其作用于线粒体，以防止启动的凋亡级联反应的生产，以保持心脏功能。利用已建立的常温和低温细胞和动物模型的组合，我们提出了两个主要的具体目标：1）确定低氧诱导的一氧化氮、活性氧（ROS）的调节和钙离子在保护心肌细胞和心脏免受缺血/再灌注（I/R）诱导的损伤中的相互作用。我们假设，缺血内低温保护涉及产生一个改变的ROS和活性氮（RNS）的配置文件，允许恢复缺血减少线粒体膜电位和阻断细胞色素c（cyt c）从线粒体的释放。在这些研究中，我们将研究特定的氧化剂，如超氧化物和一氧化氮的诱导或调制，低温和这些影响的线粒体凋亡途径的启动。2)确定线粒体Bcl-2家族蛋白（特别是Bax和巴克）与其他“靶向”蛋白（特别是p53）之间的相互作用，通过这些相互作用，低血糖诱导的NO生成提供保护并防止促凋亡线粒体蛋白cyt c的释放和半胱天冬酶的激活。我们推测I/R过程中p53的激活导致Bax和/或巴克的激活，低温阻断p53的激活、与Bax/巴克的相互作用和/或易位将抑制这些相互作用，阻断细胞色素c的释放并保护细胞免于凋亡。拟议的研究将阐明参与低温诱导心肌细胞保护的分子机制，包括“适应性”或保护性低温氧化剂概况的细节。了解特定线粒体凋亡途径受低温信号影响的机制将有助于制定低温，药理学和遗传治疗方法的最佳保护方案。