Neurovascular Protection by Adropin in Ischemic Stroke

摘要 Adropin是最近发现的一种高度保守的多肽，在大脑中大量表达。阿洛平 在调节内皮功能、胰岛素敏感性和新陈代谢方面起着关键作用。最新发现 阿罗平可以显著降低大鼠脑内皮细胞的通透性， 人血管内皮细胞。临床研究表明，低水平的血浆中 阿托品与几种人类疾病的内皮功能障碍。内皮功能障碍是关键之一 导致缺血性卒中发病的因素。一氧化氮(NO)的产生不足 内皮型一氧化氮合酶(ENOS)是糖尿病血管内皮细胞功能障碍的关键因素。 肥胖和高脂血症，这些都是中风的重要危险因素。我们的假设是阿托品能 通过减少血脑屏障(BBB)/神经血管的损伤来保护缺血性中风损伤 单位。我们在这项提案中的总体目标是证明阿托品在缺血性中风和脑梗塞中的保护作用。 研究这种保护的潜在分子机制。我们的初步数据支持这一假设 在小鼠中风模型中，合成阿洛平的治疗极大地减少了脑损伤， 这与eNOS磷酸化显著增加和血脑屏障损伤减少有关。此外， 内皮型一氧化氮合酶缺陷小鼠肾上腺素保护完全取消，提示内皮型一氧化氮合酶依赖 阿屈平在卒中中保护作用的机制。目的1是确定阿屈平的作用。 治疗缺血性卒中小鼠模型的脑梗塞范围和长期功能恢复。在目标2中，我们 将决定阿屈平减轻内皮功能障碍、氧化应激、 以及神经炎症对缺血性卒中后血脑屏障功能的影响。在目标3中，我们将测试神经保护 阿屈平的疗效与年龄、性别、种类和合并疾病(肥胖和糖尿病)有关。这是我们的 期望这项研究将为阿屈平对脑缺血的保护作用提供有意义的知识。 卒中。预计这种结果将产生重要的积极影响，因为它们将为 关于肾上腺素在脑缺血中的保护作用的扩大的临床前工作，并将确定新的 以及迫切需要的方法来减少中风后神经血管损伤的破坏性后果。

ABSTRACT Adropin is a recently identified and highly conserved polypeptide abundantly expressed in the brain. Adropin plays a critical role in the regulation of endothelial function, insulin sensitivity, and metabolism. Recent findings from our group and others reveal that adropin can significantly reduce endothelial permeability in rat brain and human vascular endothelial cells. Clinical studies show a significant association between low plasma levels of adropin and endothelial dysfunction in several human diseases. Endothelial dysfunction is one of the critical factors contributing to the pathogenesis of ischemic stroke. Deficient production of nitric oxide (NO) by endothelial nitric oxide synthase (eNOS) is a key factor contributing to endothelial dysfunction in diabetes, obesity, and hyperlipidemia, which are important risks factors for stroke. Our hypothesis is that adropin confers protection against ischemic stroke injury by reducing damage to the blood-brain barrier (BBB)/neurovascular unit. Our overall goal in this proposal is to demonstrate the protective role of adropin in ischemic stroke and investigate the underlying molecular mechanisms of this protection. Our preliminary data support this hypothesis by showing that treatment with synthetic adropin dramatically reduces brain injury in a mouse stroke model, which was associated with a significant increase in eNOS phosphorylation and reduced BBB damage. Moreover, adropin protection was completely abolished in eNOS deficient mice suggesting an eNOS-dependent mechanism underlying the protective effects of adropin in stroke. Aim 1 is to determine the effects of adropin treatment on infarct size and long-term functional recovery in a mouse model of ischemic stroke. In Aim 2, we will determine the ability of adropin to reduce the detrimental effects of endothelial dysfunction, oxidative stress, and neuroinflammation on BBB function following ischemic stroke. In Aim 3, we will test the neuroprotective efficacy of adropin in relation to age, sex, species, and comorbid conditions (obesity and diabetes). It is our expectation that this study will provide significant knowledge on the protective efficacy of adropin in ischemic stroke. Such results would be expected to have an important positive impact, since they would set the stage for expanded preclinical work on the protective efficacy of adropin in cerebral ischemia, and would identify novel and much-needed approaches to reduce the devastating consequences of neurovascular injury after stroke.