Acid, Succinate and Glyoxal Metabolism in Ischemia

缺血时的酸、琥珀酸和乙二醛代谢

• 批准号: 10585980
• 负责人: Paul S Brookes
• 金额: $ 41.95万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585980
• 关键词: ATP Synthesis Pathway; Ablation; Acids; Acute; Acute myocardial infarction; Address; Adult; Alkynes; Angioplasty; Biological Process; Cardiac Myocytes; Cardiac Surgery procedures; Cardiotonic Agents; Cell Membrane Permeability; Chemistry; Chronic; Complex; Diabetes Mellitus; Dioxygenases; Electron Transport; Electron Transport Complex III; Engineering; Enzymes; Event; FDA approved; Feedback; Fluorescence; Funding; Generations; Glucose; Glycolysis; Glyoxal; Heart; Heart Injuries; High Fat Diet; Hyperglycemia; In Situ; Insulin; Intervention; Ischemia; Ischemic Preconditioning; Knowledge; Mediating; Metabolic; Metabolic acidosis; Metabolism; Mitochondria; Modeling; Mus; Myocardial Infarction; Myocardial Ischemia; Necrosis; Organ; Outcome; Paper; Pathologic; Pathology; Patients; Perfusion; Pharmaceutical Chemistry; Pharmaceutical Preparations; Potassium; Proteins; Proteomics; Publishing; Pyruvaldehyde; Reactive Oxygen Species; Recombinants; Regulation; Reperfusion Injury; Reperfusion Therapy; Research; Role; Schedule; Signal Transduction; Societies; Stress; Succinates; Supplementation; System; Testing; Therapeutic; Tissues; Work; alpha ketoglutarate; cardioprotection; diabetic; gluconolactone oxidase; heart metabolism; in vivo; inhibitor; innovation; insight; ischemic injury; metabolomics; mitochondrial permeability transition pore; myocardial injury; novel; overexpression; oxidation; programs; sexual dimorphism; small molecule inhibitor; small molecule therapeutics; thrombolysis; type I diabetic; ATP Synthesis Pathway; Ablation; Acids; Acute; Acute myocardial infarction; Address; Adult; Alkynes; Angioplasty; Biological Process; Cardiac Myocytes; Cardiac Surgery procedures; Cardiotonic Agents; Cell Membrane Permeability; Chemistry; Chronic; Complex; Diabetes Mellitus; Dioxygenases; Electron Transport; Electron Transport Complex III; Engineering; Enzymes; Event; FDA approved; Feedback; Fluorescence; Funding; Generations; Glucose; Glycolysis; Glyoxal; Heart; Heart Injuries; High Fat Diet; Hyperglycemia; In Situ; Insulin; Intervention; Ischemia; Ischemic Preconditioning; Knowledge; Mediating; Metabolic; Metabolic acidosis; Metabolism; Mitochondria; Modeling; Mus; Myocardial Infarction; Myocardial Ischemia; Necrosis; Organ; Outcome; Paper; Pathologic; Pathology; Patients; Perfusion; Pharmaceutical Chemistry; Pharmaceutical Preparations; Potassium; Proteins; Proteomics; Publishing; Pyruvaldehyde; Reactive Oxygen Species; Recombinants; Regulation; Reperfusion Injury; Reperfusion Therapy; Research; Role; Schedule; Signal Transduction; Societies; Stress; Succinates; Supplementation; System; Testing; Therapeutic; Tissues; Work; alpha ketoglutarate; cardioprotection; diabetic; gluconolactone oxidase; heart metabolism; in vivo; inhibitor; innovation; insight; ischemic injury; metabolomics; mitochondrial permeability transition pore; myocardial injury; novel; overexpression; oxidation; programs; sexual dimorphism; small molecule inhibitor; small molecule therapeutics; thrombolysis; type I diabetic

ABSTRACT In the US there are >700,000 new heart attacks (acute myocardial infarctions) a year, and >300,000 patients undergo scheduled ischemia during cardiac surgery. Beyond tissue reperfusion (angioplasty, thrombolysis) there are no FDA-approved interventions to limit acute cardiac injury due to ischemia and reperfusion (IR). This renewal proposal supports our ongoing research program in cardiac metabolism, and is focused on novel cardioprotective metabolic signaling events downstream of glycolysis. It is built on the following premise: (i) Acidic pH during IR is cardioprotective, and many therapies that boost glycolysis work in-part by enhancing metabolic acidosis. (ii) Succinate accumulation is a key event in ischemia, and its oxidation at reperfusion drives reactive oxygen species generation. We propose acid can regulate succinate dynamics (accumulation, oxidation, transport). (iii) The glycolytic byproduct methylglyoxal (MGO) causes glycative stress in diabetes, but type-I diabetic hearts are acutely protected against IR injury, and MGO inhibits the mitochondrial permeability transition (PT) pore, a key event in IR injury. Some cardioprotective interventions also elevate MGO. (iv) The mitochondrial enzyme ALKBH7 is necessary for necrosis. Inhibition or ablation of ALKBH7 is cardioprotective, and this protection requires the MGO metabolizing enzyme GLO-1. Based on these published and preliminary findings, our central hypothesis is that the cardioprotective effects of elevated glycolysis are mediated by pH, succinate, and MGO. This hypothesis will be tested by addressing 3 related aims… Aim 1 will investigate succinate dynamics in IR injury and the impact of pH. Aim 2 will investigate the role of MGO as an acute cardioprotective signal, including identifying its targets in mitochondria. Aim 3 will study ALKBH7, identify its substrates, and develop ALKBH7 inhibitors as cardioprotective drugs. The aims will use established experimental systems (adult cardiomyocytes, perfused hearts, LC-MS based metabolomics, in-vivo IR injury, and a high-fat diet model of diabetes) and engineered mice including Alkbh7-/-, Glo1-/- and hGlo1TG. Innovation is embedded in the idea that MGO can serve an acute protective signaling role separate from its well-known chronic pathologic effects (i.e. hormesis). This work will advance basic knowledge on ischemic cardiac metabolism, will develop small molecule therapeutics, and will offer mechanistic insights to other pathologies beyond IR.

抽象的 在美国，每年有> 700,000个新的心脏病发作（急性心肌违规），> 300,000名患者 心脏手术期间预定的缺血。超越组织再灌注（血管成形术，溶栓） 没有FDA批准的干预措施，以限制缺血和再灌注（IR）引起的急性心脏损伤。 更新建议支持我们正在进行的心脏代谢研究计划，并专注于新颖 糖酵解下游的心脏保护代谢信号事件。它建立在以下前提下：（i） IR期间的酸性pH是心脏保护性的，许多疗法可以通过增强来促进糖酵解的作用 代谢性酸中毒。 （ii）琥珀酸酯的积累是缺血的关键事件，其再灌注时的氧化 驱动活性氧的产生。我们建议酸可以调节琥珀酸酯动力学（积累， 氧化，运输）。 （iii）糖酵解副产品甲基乙醛（MGO）会导致糖尿病的糖质量，但 I型糖尿病心脏受到急性保护，免受IR损伤，MGO抑制线粒体渗透性 过渡（PT）孔，IR损伤的关键事件。一些心脏保护干预措施也提升了MGO。 （iv） 线粒体酶ALKBH7对于坏死是必需的。抑制或消融ALKBH7是心脏保护性的， 这种保护需要MGO代谢酶GLO-1。基于这些已发表的初步 调查结果是，我们的中心假设是介导升高糖酵解的心脏保护作用 pH，琥珀酸酯和Mgo。该假设将通过解决3个相关目标来检验……目标1将 研究IR损伤中的琥珀酸酯动力学和pH的影响。 AIM 2将调查MGO的作用 急性心脏保护信号，包括识别其在线粒体中的靶标。 AIM 3将研究ALKBH7，确定 它的底物，并形成ALKBH7抑制剂作为心脏保护药物。目的将使用已建立的 实验系统（成人心肌细胞，灌注心脏，基于LC-MS代谢组学，体内IR损伤， 以及糖尿病的高脂饮食模型和工程小鼠，包括Alkbh7 - / - ，Glo1 - / - 和HGLO1TG。创新 嵌入了MGO可以发挥急性保护的信号传导作用的想法中 慢性病理效应（即刺激）。这项工作将提高缺血性心脏的基本知识 代谢，将发展小分子疗法，并将为其他病理提供机械见解 超越IR。