Nitroalkene-Mediated Vascular Protection and Ischemic Stroke

硝基烯烃介导的血管保护和缺血性中风

• 批准号: 8311616
• 负责人: YUQING Eugene CHEN
• 金额: $ 34.02万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8311616
• 关键词: 2,4-thiazolidinedione; Adult; Adverse effects; Affect; Behavior; Binding; Blood Vessels; Brain; Brain Injuries; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cells; Cerebral Ischemia; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrum; Data; Development; Diabetes Mellitus; Drug Design; Edema; Event; Exposure to; Glucose; Hepatotoxicity; Human; Hypertension; In Vitro; Infarction; Inflammation; Inflammatory; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Laboratories; Lead; Ligands; Link; Linoleic Acids; Mediating; Mediator of activation protein; Middle Cerebral Artery Occlusion; Modeling; Molecular; Mus; Neurons; Nitrates; Nitric Oxide; Obesity; Oleic Acids; Outcome; Oxygen; Pathogenesis; Patients; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Physiological; Plasma; Play; Reaction; Receptor Signaling; Receptor, Angiotensin, Type 1; Recovery of Function; Regulation; Reporting; Risk Factors; Rodent Model; Role; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Stroke; Testing; Therapeutic; Thiazolidinediones; Time; Transgenes; United States; Vascular Diseases; Vascular Endothelial Cell; Weight Gain; base; cell type; deprivation; disability; drug development; effective therapy; improved; in vivo; insight; mortality; nitroalkene; novel therapeutics; protective effect; receptor; receptor function; receptor-mediated signaling; treatment strategy; vascular inflammation

DESCRIPTION (provided by applicant): Ischemic stroke results from a transient or permanent local reduction of cerebral blood flow, characterized by a set of cellular disturbances. With a mortality rate of 30%, stroke is the third leading causes of death and the leading cause of adult disability in the United States. Unfortunately, development of effective therapies is seriously limited by the rapid development of irreversible brain injury following ischemia. Recently, increasing data suggest that peroxisome proliferator- activated receptor-3 (PPAR3) and angiotensin II (Ang II) type 1 receptor (AT1R) are two critical mediators in the pathogenesis of ischemic brain damage. Nitrated oleic acid (OA-NO2) and linoleic acid (LNO2), nitroalkenes formed in nitric oxide (NO)-dependent oxidative reactions, have been found in human plasma and are thought to regulate physiological functions in multiple cell types. Of significance, we have shown that both OA-NO2 and LNO2 are the endogenous PPAR3 ligands. Also, our preliminary studies have documented for the first time that intracerebroventricular administration of OA-NO2 can reduce cerebral infarct volume and edema in mice after 24h of middle cerebral artery (MCA) occlusion. Moreover, we have found that OA-NO2 can bind to AT1R and inhibit its signaling in vascular smooth muscle cells (VSMCs). Furthermore, we have also found that OA-NO2 can inhibit inflammatory reaction in cerebral VSMCs and cerebral vascular endothelial cells (CECs) after exposure to Oxygen Glucose Deprivation (OGD). These findings suggest that nitroalkenes play a critical protective role in ischemic brain damage. In this proposal, we will test the central hypothesis that nitroalkenes (e.g. OA-NO2) may inhibit cerebral ischemia-induced vascular inflammation to exert neuronal protective effects by inhibition of the AT1R signaling pathway and activation of PPAR3-dependent cascade. Specifically, we will define 1) that OA-NO2 inhibits OGD-induced inflammation in cerebral vascular cells via AT1R and PPAR3 signaling pathways; 2) that vascular- selective activation of PPAR3 contributes to the neuronal protection of OA-NO2 in ischemic stroke; 3) that vascular-selective inhibition of AT1R signaling contributes to the neuronal protection of OA-NO2 in ischemic stroke. It is anticipated that elucidating the mechanism of OA-NO2-mediated brain protection in cerebral ischemia will lead to a better understanding of endogenous signaling actions of nitroalkenes in ischemic stroke and will set strong basis for new perspectives on rational drug design and development of nitroalkene derivatives for the treatment of stroke.

描述（由申请人提供）：缺血性中风是由于瞬时或永久性局部减少脑血流的原因，其特征是一组细胞障碍。中风的死亡率为30％，是美国第三大死亡原因，是美国成人残疾的主要原因。不幸的是，缺血后不可逆的脑损伤的快速发展受到有效疗法的发展受到严重限制。最近，增加的数据表明，过氧化物酶体增殖物激活的受体-3（PPAR3）和血管紧张素II（ANG II）1型受体（AT1R）是缺血性脑损伤发病机理的两个关键介质。硝化油酸（OA-NO2）和亚油酸（LNO2），在人血浆中发现了一氧化氧化物（NO）依赖性氧化反应，并被认为可以调节多种细胞类型的生理功能。重要的是，我们已经表明OA-NO2和LNO2都是内源性PPAR3配体。同样，我们的初步研究首次记录了OA-NO2的脑室内给药可以减少脑动脉24小时后小鼠的脑梗塞体积和水肿（MCA）闭塞。此外，我们发现OA-NO2可以与AT1R结合并抑制其在血管平滑肌细胞（VSMC）中的信号传导。此外，我们还发现，在暴露于氧气葡萄糖剥夺（OGD）后，OA-NO2可以抑制脑VSMC和脑血管内皮细胞（CEC）的炎症反应。这些发现表明，硝基烯烃在缺血性脑损伤中起着至关重要的保护作用。在该提案中，我们将检验一个中心假设：硝基烷烃（例如OA-NO2）可能会抑制脑缺血诱导的血管炎症，从而通过抑制AT1R信号通路和PPAR3依赖性级联的激活来抑制神经元保护作用。具体而言，我们将定义1）OA-NO2通过AT1R和PPAR3信号通路抑制OGD诱导的脑血管细胞的炎症； 2）PPAR3的血管选择性激活有助于OA-NO2在缺血性中风中的神经元保护； 3）血管选择性抑制AT1R信号传导有助于OA-NO2在缺血性中风中的神经元保护。可以预料，阐明脑缺血中OA-NO2介导的脑部保护的机制将使人们更好地了解硝基烷烃在缺血性中风中的内源信号传导作用，并将为硝基烷衍生物的理性药物设计和硝基烷衍生物的开发提供强有力的基础，以治疗Streoke的治疗。