Acid, Succinate and Glyoxal Metabolism in Ischemia

缺血时的酸、琥珀酸和乙二醛代谢

基本信息

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
项目类别：
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

项目摘要

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，每年有超过 700,000 例新发心脏病（急性心肌梗塞），并且有超过 300,000 名患者在心脏手术期间经历预定的缺血（除了组织再灌注（血管成形术、溶栓术））。目前尚无 FDA 批准的干预措施来限制缺血再灌注 (IR) 引起的急性心脏损伤。更新提案支持我们正在进行的心脏代谢研究项目，并专注于新颖的糖酵解下游的心脏保护性代谢信号事件建立在以下前提之上：（i） IR 期间的酸性 pH 值具有心脏保护作用，许多促进糖酵解的疗法部分通过增强 (ii) 琥珀酸盐积累是缺血及其再灌注时氧化的关键事件。我们认为酸可以调节琥珀酸盐的动力学（积累， (iii) 糖酵解副产物甲基乙二醛 (MGO) 会导致糖尿病的糖化应激，但是 I 型糖尿病心脏可免受 IR 损伤，MGO 可抑制线粒体通透性过渡 (PT) 孔是 IR 损伤的一个关键事件，一些心脏保护干预措施也会提高 MGO。线粒体酶 ALKBH7 对于坏死是必需的，抑制或消除 ALKBH7 具有心脏保护作用。而这种保护需要 MGO 代谢酶 GLO-1 基于这些已发表的和初步的研究。研究结果表明，我们的中心假设是糖酵解升高的心脏保护作用是通过介导的该假设将通过解决 3 个相关目标进行检验……目标 1 将研究 IR 损伤中的琥珀酸动态以及 pH 的影响，目标 2 将研究 MGO 作为一种药物的作用。急性心脏保护信号，包括识别其在线粒体中的靶点，目标 3 将研究 ALKBH7，识别其目标。其底物，并开发 ALKBH7 抑制剂作为心脏保护药物。实验系统（成人心肌细胞、灌注心脏、基于 LC-MS 的代谢组学、体内 IR 损伤、和糖尿病高脂饮食模型）以及工程小鼠，包括 Alkbh7-/-、Glo1-/- 和 hGlo1TG。 MGO 可以发挥急性保护信号作用，与其众所周知的作用不同。慢性病理效应（即兴奋作用）这项工作将增进对缺血性心脏的基础知识。新陈代谢，将开发小分子疗法，并将为其他病理学提供机制见解超越红外。