Vascular dysfunction in coronary microcirculation

摘要 心血管疾病导致美国34%的死亡， 美国人患有冠心病。其中，850万经验 心肌梗死尽管我们在理解 心脏再灌注损伤的机制，我们还没有找到有效的干预措施， 减轻I/R损伤。一氧化氮（NO）在舒张冠状动脉中起重要作用， 微循环是重要的运输氧气和营养物质的心肌组织。它 已经证明，一氧化氮合酶（eNOS），产生NO的酶， 在I/R中，血管内皮中的超氧阴离子发生改变，并产生有害的超氧阴离子 自由基，它不仅通过与NO反应来消耗NO，而且还产生更多有害的 活性氮有趣的是，在我们的初步研究中，我们发现eNOS是 I/R后心肌组织中谷胱甘肽化并进行性丢失。我们 假设eNOS在I/R期间经历S-谷胱甘肽化， 分子伴侣介导的自噬，导致NO产生的不可逆损失， 冠状动脉微循环和灌注导致I/R心肌梗死（MI）。在 目的1探讨S-腺苷酸诱导血管内皮型一氧化氮合酶（eNOS）表达缺失的机制。 谷胱甘肽化在目标2中，我们将研究参与的特定类型的自噬， eNOS消失;在目标3中，我们将阐明eNOS自噬并评估 硫氧还蛋白的去谷胱甘肽化是否会改善再灌注损伤， 各种转基因和基因敲除小鼠模型。我们的研究将提供一个 明确eNOS在I/R中丢失的冠状动脉血管机制的作用。 这项研究的结果可能为临床管理提供重要的见解， 并开发新的介入治疗再灌注损伤。

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.