Nitrite Mediated Cardioprotection

亚硝酸盐介导的心脏保护作用

• 批准号: 8289582
• 负责人: DAVID JOSEPH LEFER
• 金额: $ 25.42万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8289582
• 关键词: Acute; Acute myocardial infarction; Affect; Apoptosis; Apoptotic; Biochemical; Biological Availability; Biological Models; Calcium; Cardiac; Cardiovascular Diseases; Cell Death; Cessation of life; Data; Dietary Nitrite; Dose; Event; Experimental Models; Flavin Mononucleotide; Flavin-Adenine Dinucleotide; Gases; Gene Targeting; Generations; Healthcare; Heart; Heme; Hypoxia; Intake; Ischemia; Leukocyte Chemotaxis; MAP Kinase Gene; Mediating; Mitochondria; Molecular; Mus; Mutation; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial Ischemic Preconditioning; Myocardium; Myoglobin; N,N-dimethylarginine; Nitrates; Nitric Oxide; Nitric Oxide Donors; Nitrite Reductase; Nitrites; Oral; Outcome; Oxidative Stress; Oxygen; Pathway interactions; Physiological; Platelet aggregation; Property; Proteins; Reperfusion Injury; Reperfusion Therapy; Respiration; Role; Severities; Signal Transduction; Signaling Molecule; Structure; Sulfhydryl Compounds; Supplementation; Testing; Therapeutic; Therapeutic Agents; Tissues; Troponin I; United States; Vasodilation; clinically relevant; cofactor; dietary restriction; drinking water; in vivo; indexing; inhaled nitric oxide; inhibitor/antagonist; intravenous administration; myocardial infarct sizing; novel; novel therapeutics; overexpression; public health relevance; research study; tetrahydrobiopterin; treatment strategy

DESCRIPTION (provided by applicant): Nitric oxide (NO) has been extensively studied in the setting of ischemia-reperfusion (I/R) injury. Previous studies clearly demonstrate that the deficiency of eNOS exacerbates myocardial I/R injury whereas the overexpression of eNOS, NO donor or inhaled NO gas therapy significantly protect the myocardium. NO possesses a number of physiological properties that makes it a potent cardioprotective-signaling molecule. These include vasodilation and the inhibition of oxidative stress, platelet aggregation, leukocyte chemotaxis and apoptosis. The synthesis of NO is critically influenced by various cofactors such as tetrahydrobiopterin, flavin mononucleotide and flavin adenine dinucleotide, the presence of reduced thiols, and the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA), as well as, substrate and oxygen availability. Without an adequate delivery of substrate and co-factors (conditions that certainly exist in the heart during ischemia), NOS is no longer able to produce NO. Therefore, alternate means to produce NO in ischemic tissues are needed to limit I/R injury. Previous studies in our lab have shown that an acute administration of nitrite protects against myocardial I/R injury. Additionally, our preliminary data demonstrates that modest changes in dietary nitrite intake significantly alter steady-state concentrations of nitrite, nitroso modified proteins, and nitrosyl-heme products and that these biochemical changes have a profound outcome on the severity of acute myocardial infarction. Furthermore, our preliminary data suggests that the observed cardioprotection is mediated, in part, by the reduction of nitrite to NO during both the oral supplementation and ischemic periods. The objective of this proposal is to test the overall hypothesis that nitrite serves as an endogenous storage form of NO that renders cardioprotection through its ability to be converted to NO. To test this hypothesis, we have proposed the following four Specific Aims. Specific Aim 1 will investigate the optimal therapeutic strategy needed to achieve cardioprotection in the setting of myocardial I/R by evaluating different doses and durations of nitrite supplementation. Specific Aim 2 will begin our mechanistic studies of nitrite supplementation therapy by investigating the reduction of nitrite to NO by myoglobin. Specific Aim 3 will investigate some of the molecular mechanisms of nitrite supplementation therapy, including the effects of nitrite on the apoptotic pathway following myocardial I/R. Specific aim 4 will investigate the effects of oral nitrite therapy on the structure and function of mitochondria following myocardial I/R. Public Health Relevance: Despite numerous advances in health care, cardiovascular disease remains the number one killer in the United States and acute myocardial infarction (i.e., heart attack) affects nearly 1.1 million people every year and is responsible for approximately 220,000 deaths per year. The proposed studies will evaluate the protective actions of a novel therapeutic agent (i.e., oral nitrite therapy) in a clinically relevant experimental model system of acute myocardial infarction. The proposed studies will significantly advance our current understanding of the mechanisms responsible for myocardial cell death during a heart attack

描述（由申请人提供）：一氧化氮（NO）在缺血-再灌注（I/R）损伤的情况下已被广泛研究。以往的研究清楚地表明，eNOS的缺乏加剧了心肌I/R损伤，而eNOS的过表达、NO供体或吸入NO气体治疗对心肌具有显著的保护作用。NO具有许多生理特性，使其成为一种有效的心脏保护信号分子。这些包括血管舒张和抑制氧化应激、血小板聚集、白细胞趋化性和细胞凋亡。NO的合成受到各种辅助因子如四氢生物蝶呤、黄素单核苷酸和黄素腺嘌呤二核苷酸、还原硫醇的存在、内源性NOS抑制剂不对称二甲基精氨酸（ADMA）以及底物和氧可用性的严重影响。如果没有足够的底物和辅因子（缺血期间心脏中确实存在的条件），NOS不再能够产生NO。因此，需要在缺血组织中产生NO的替代方法来限制I/R损伤。我们实验室以前的研究表明，急性给予亚硝酸盐可保护心肌I/R损伤。此外，我们的初步数据表明，饮食中亚硝酸盐摄入量的适度变化显着改变亚硝酸盐，亚硝基修饰蛋白质和亚硝基血红素产品的稳态浓度，这些生化变化对急性心肌梗死的严重程度有深远的影响。此外，我们的初步数据表明，所观察到的心脏保护是介导的，在一定程度上，通过在口服补充剂和缺血期间将亚硝酸盐还原为NO。本提案的目的是检验以下总体假设：亚硝酸盐作为NO的内源性储存形式，通过其转化为NO的能力提供心脏保护。为了检验这一假设，我们提出了以下四个具体目标。具体目标1将通过评估不同剂量和持续时间的亚硝酸盐补充来研究在心肌I/R环境中实现心脏保护所需的最佳治疗策略。具体目标2将通过研究肌红蛋白将亚硝酸盐还原为NO来开始我们的亚硝酸盐补充疗法的机制研究。具体目标3将研究亚硝酸盐补充疗法的一些分子机制，包括亚硝酸盐对心肌I/R后细胞凋亡途径的影响。具体目标4将研究口服亚硝酸盐治疗对心肌I/R后线粒体结构和功能的影响。公共卫生相关性：尽管在医疗保健方面取得了许多进展，但心血管疾病仍然是美国的头号杀手，而急性心肌梗死（即，心脏病发作）每年影响近110万人，并造成每年约220，000人死亡。拟议的研究将评估一种新型治疗剂的保护作用（即，口服亚硝酸盐疗法）在急性心肌梗塞的临床相关实验模型系统中的应用。这项研究将大大推进我们目前对心脏病发作期间心肌细胞死亡机制的理解