Vascular dysfunction in coronary microcirculation

摘要 心血管疾病导致的死亡占美国所有死亡人数的34%和1760万人 美国人患有冠心病(CHD)。其中，850万次体验 心肌梗死。尽管我们在理解 心脏再灌注损伤的机制，目前还没有找到有效的干预措施 减轻I/R损伤。一氧化氮(NO)在冠脉松弛中起重要作用 微循环对于将氧气和营养物质输送到心肌组织非常重要。它 已经证明，一氧化氮合酶(ENOS)是一种产生NO的酶 血管内皮细胞在I/R时发生改变，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，而且产生更多的有害物质 活性氮物种。有趣的是，在我们的初步研究中，我们发现eNOS是 缺血再灌注后心肌组织中谷胱甘肽逐渐丢失。 假设eNOS在I/R过程中经历S谷胱甘肽基化，从而诱导其 伴侣介导的自噬，导致影响NO产生的不可逆转的损失 冠脉微循环和灌注导致I/R心肌梗死 目的1探讨S致血管内皮源性一氧化氮合酶丢失的机制。 谷胱甘肽基化。在目标2中，我们将调查涉及的特定类型的自噬 ENOS消失；在目标3中，我们将阐明eNOS自噬并评估 硫氧还蛋白对谷胱甘肽的氧化作用是否会改善再灌注损伤 各种转基因和基因敲除小鼠模型。我们提议的研究将提供一个 明确冠脉血管内皮细胞eNOS丢失在I/R中的作用机制。 这项研究的结果可能为临床治疗提供重要的见解。 心肌梗死和开发治疗再灌注损伤的新干预措施。

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.