Vascular dysfunction in coronary microcirculation

冠状动脉微循环血管功能障碍

• 批准号: 10539280
• 负责人: KUMUDA C DAS
• 金额: $ 63.49万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-10 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10539280
• 关键词: Acute; Adenine; Affect; American; Apoptosis; Autophagocytosis; Blood Vessels; Blood flow; Cardiovascular Diseases; Cells; Cessation of life; Clinical Management; Clinical Trials; Coronary; Coronary artery; Coronary heart disease; Data; Degradation Pathway; Development; Endothelial Cells; Enzymes; Event; Generations; Heart; Heart Injuries; Heart failure; Human; Hypoxia; Impairment; Infarction; Injury; Intervention; Ischemia; Knockout Mice; Lysosomes; MG132; Mediating; Microcirculation; Molecular Chaperones; Morbidity - disease rate; Mouse Strains; Mus; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardial perfusion; Myocardial tissue; Myocardium; NOS3 gene; Necrosis; Nitric Oxide; Nitric Oxide Synthase; Nutrient; Oxidoreductase; Oxygenases; Pathway interactions; Patients; Perfusion; Play; Population; Production; Prognostic Factor; Proteins; Reaction; Reactive Nitrogen Species; Relaxation; Reperfusion Injury; Reperfusion Therapy; Research; Role; Signal Transduction; Superoxides; TXN gene; Testing; Time; Transfection; Transgenic Mice; Transgenic Organisms; United States; Vascular Diseases; Vascular Endothelium; coronary artery occlusion; coronary perfusion; effective intervention; experience; improved; in vivo; inhibition of autophagy; inhibitor; insight; mortality; mouse model; multicatalytic endopeptidase complex; mutant; novel; novel therapeutics; oxidation; oxygen transport; tetrahydrobiopterin; translational model

Abstract Cardiovascular disease causes 34% of all deaths in the United States and 17.6 million Americans suffer from coronary heart disease (CHD). Of these, 8.5 million experience myocardial infarction. Although we have made significant progress in understanding the mechanisms of reperfusion injury of heart, we are yet to find an effective intervention to alleviate I/R injury. Nitric oxide (NO) plays a major role in relaxation of coronary microcirculation that is important to transport oxygen and nutrients to myocardial tissue. It has been demonstrated that nitric oxide synthase (eNOS), the enzyme that generates NO in the vascular endothelium is altered in I/R and produces deleterious superoxide anion radical, which not only depletes NO by reacting with it, but also produces more harmful reactive nitrogen species. Intriguingly, in our preliminary studies we found that eNOS is glutathionylated and progressively lost in the myocardial tissue following I/R. We hypothesize that eNOS undergoes S-glutathionylation during I/R that induces its chaperone mediated autophagy, resulting in irreversible loss of NO production that affects coronary microcirculation and perfusion resulting in myocardial infarction (MI) in I/R. In Aim 1 we will investigate the mechanism of loss of vascular eNOS due to S- glutathionylation. In Aim 2, we will investigate the specific type of autophagy involved in eNOS disappearance; and in Aim 3 we will elucidate the eNOS autophagy and evaluate whether deglutathionylation by thioredoxin would ameliorate reperfusion injury, using a variety of transgenic and knockout mice models. Our proposed research will provide a clear understanding of the role of coronary vascular mechanism of loss of eNOS in I/R. The results of this study may provide significant insight into clinical management of myocardial infarction and develop new intervention for treatment of reperfusion injury.

抽象的 心血管疾病造成34％的美国死亡，1,760万 美国人患有冠心病（CHD）。其中850万经验 心肌梗塞。尽管我们在理解 心脏再灌注损伤的机制，我们尚未找到有效的干预措施 减轻I/R受伤。一氧化氮（NO）在冠状动脉放松中起主要作用 微循环对于将氧气和养分运输到心肌组织很重要。它 已经证明一氧化氮合酶（eNOS）是生成无的酶 在血管内皮中，I/R中的内皮发生了变化，并产生有害的超氧化阴离子 激进分子，不仅可以通过与之反应来耗尽否，而且还会产生更有害的 反应性氮种。有趣的是，在我们的初步研究中，我们发现eNOS是 I/R之后，在心肌组织中谷胱甘肽化并逐渐损失。我们 假设eNOS在I/R期间经历S-谷氨酸的诱导 伴侣介导的自噬，导致不可逆转的无生产损失 冠状动脉微循环和灌注导致心肌梗塞（MI）在I/R中。在 AIM 1我们将研究由于S-引起的血管eNOS丧失的机制 谷胱甘肽化。在AIM 2中，我们将研究涉及的特定类型的自噬类型 eNOS消失；在AIM 3中，我们将阐明eNOS自噬并评估 硫氧还蛋白通过硫氧还蛋白的脱脂二硫代化是否会使用A来改善再灌注损伤 各种转基因和敲除小鼠模型。我们拟议的研究将提供 清楚地了解I/R中eNOS丧失的冠状动脉血管机理的作用。 这项研究的结果可能会对临床管理的重大见解 心肌梗塞并开发新的干预措施来治疗再灌注损伤。