Role of nitro-fatty acids in BBB stabilization and post-stroke neurovascular protection

硝基脂肪酸在血脑屏障稳定和中风后神经血管保护中的作用

• 批准号: 10514600
• 负责人: Kejie Yin
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10514600
• 关键词: Adult; Affect; Age; Aging; Anti-Inflammatory Agents; Astrocytes; Atherosclerosis; Attenuated; Blood - brain barrier anatomy; Blood Preservation; Blood Proteins; Blood brain barrier dysfunction; Brain; Brain Infarction; Brain Injuries; Cardiovascular system; Cause of Death; Cells; Cerebral Ischemia; Cerebrum; Coculture Techniques; Data; Development; Diabetes Mellitus; Edema; Endothelial Cells; Event; Extravasation; Fatty Acids; Functional disorder; Genes; Genetic; Glucose; Hemorrhage; Hospitalization; Human; Immune; Impairment; In Vitro; Inflammation; Inflammation Mediators; Inflammatory Response; Injury; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Ligands; Macrophage; Maintenance; Mediating; Mediator; Medical; Middle Cerebral Artery Occlusion; Modeling; Molecular; Mus; Myocardial Ischemia; Neurologic; Neurologic Deficit; Neurologic Dysfunctions; Neurological outcome; Nitric Oxide; Nitrogen Dioxide; Oleic Acids; Outcome; Oxygen; PPAR gamma; Pathogenesis; Pathologic; Pathway interactions; Peripheral; Permeability; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Pharmacologic Substance; Physiological; Plasma; Play; Publications; Reaction; Recovery; Regulation; Reperfusion Injury; Reperfusion Therapy; Rodent; Role; Signal Pathway; Signal Transduction; Stroke; Survivors; Testing; Therapeutic; Therapeutic Intervention; Thrombolytic Therapy; Tight Junctions; Time; United States; Veterans; blood-brain barrier disruption; brain endothelial cell; cell type; cerebrovascular; deprivation; disability; effective therapy; functional improvement; genetic manipulation; immune cell infiltrate; improved; intravenous administration; mRNA Expression; migration; neurobehavior; neurobehavioral; neuron loss; neurovascular; neurovascular injury; nitroalkene; novel; pharmacologic; post stroke; prevent; protein expression; renal ischemia; therapeutically effective; transcriptome sequencing; vascular inflammation

Stroke is one of the major medical concerns for United States veterans. At least 15,000 veterans are hospitalized every year for stroke and most survivors live with long-term neurological impairments. Unfortunately, development of effective therapies is seriously limited. Extensive studies have shown that BBB breakdown promotes a devastating cascade of events, contributing to transmigration of peripheral immune cells, cerebral inflammatory responses, edema, hemorrhagic transformation, neuronal loss and eventual neurological deficits after cerebral ischemia/reperfusion (I/R). Thus, it is necessary to identify mechanisms and develop effective therapeutic strategies that protect BBB integrity and prevent permanent neurovascular injury after I/R. Nitro-oleic acid (OA-NO2), a nitroalkene formed in nitric oxide (NO)-dependent oxidative reactions, has been found in human plasma and is thought to be a novel cell signaling mediator that regulates physiological functions in multiple cell types. It has been shown that OA-NO2 is an endogenous peroxisome proliferator- activated receptor-γ (PPARγ) ligand and activates PPARγ at physiological levels. Recent data have shown that OA-NO2 significantly reduces peripheral vascular inflammation and endoluminal vessel injury. Provocatively, several publications have documented that OA-NO2 is increased under ischemia-reperfusion conditions and attenuates cardiac or renal ischemia/reperfusion injury. However, the functional significance and molecular mechanisms of OA-NO2 in regulating cerebrovascular pathogenesis, in particular BBB disruption, and resultant neurological outcomes remain unexplored in ischemic stroke. In our preliminary studies, we have recently identified for the first time that intravenous (i.v.) administration of OA-NO2 leads to reuced BBB leakage, smaller brain infarction, and improved neurobehavior in mice after middle cerebral artery occlusion (MCAO). Moreover, we found that OA-NO2 significantly elevates the mRNA and protein expression of major BBB tight junctions in cultured brain microvascular endothelial cells (BMECs). These findings suggest that nitroalkenes may play a critical neurovascular protective role in ischemic brain damage. In this proposal, we will test our Central Hypothesis that OA-NO2 preserves BBB integrity after I/R via activation of PPARγ and other signaling pathways, attenuates BBB disruption and subsequent pathological cascades, thereby eliciting neurovascular protection. Three aims will be performed in this proposal. Aim 1: Define the role of OA-NO2 in BBB dysfunction/recovery and brain injury after ischemic stroke; Aim 2: Elucidate the mechanisms of OA-NO2 regulation of post-stroke BBB dysfunction/recovery; Aim 3: Explore systematic delivery of OA-NO2 as a potential BBB stabilizing therapy in ischemic stroke. Elucidating the molecular mechanisms of OA-NO2-mediated BBB stabilization and recovery may lead us to discover novel pharmaceutical approaches for the effective treatment against ischemic stroke.

中风是美国退伍军人的主要医疗问题之一。至少有15，000名退伍军人 每年都有患者因中风住院，大多数幸存者患有长期的神经损伤。 不幸的是，有效疗法的开发受到严重限制。大量研究表明，BBB 破坏促进了一系列毁灭性的事件，导致外周免疫细胞的迁移， 细胞，脑炎症反应，水肿，出血性转化，神经元丢失和最终 脑缺血/再灌注（I/R）后神经功能缺损。因此，有必要确定机制， 制定有效的治疗策略，保护BBB的完整性，防止永久性神经血管损伤 I/R后 硝基油酸（OA-NO2）是一种在一氧化氮（NO）依赖性氧化反应中形成的硝基烯烃， 在人血浆中发现，被认为是一种新的细胞信号传导介质， 在多种细胞类型中发挥作用。研究表明，OA-NO2是一种内源性过氧化物酶体增殖剂， 活化受体-γ（PPARγ）配体并在生理水平活化PPARγ。最近的数据显示， OA-NO2显著降低外周血管炎症和腔内血管损伤。挑衅地说， 一些出版物已经证明，在缺血-再灌注条件下，OA-NO2增加， 减轻心脏或肾缺血/再灌注损伤。然而，功能意义和分子 OA-NO2在调节脑血管发病机制，特别是BBB破坏中的作用机制， 缺血性卒中的神经学结局尚未探索。 在我们的初步研究中，我们最近首次发现静脉内（i. v.）管理 OA-NO2可减少BBB渗漏，减少脑梗死，改善小鼠的神经行为。 大脑中动脉闭塞（MCAO）。此外，我们发现OA-NO2显著提高了mRNA水平， 以及培养的脑微血管内皮细胞（BMEC）中主要BBB紧密连接的蛋白表达。 这些结果表明，硝基烯烃类化合物可能在缺血脑中发挥重要的神经血管保护作用 损害在本提案中，我们将测试我们的中心假设，即OA-NO2在I/R后保持BBB完整性 通过激活PPARγ和其他信号通路，减弱BBB破坏和随后的 病理级联反应，从而引发神经血管保护。三个目标将在此执行 提议目的1：明确OA-NO2在缺血性脑卒中后血脑屏障功能障碍/恢复和脑损伤中的作用; 目的2：阐明OA-NO2调节脑卒中后BBB功能障碍/恢复的机制;目的3： 探索OA-NO2的系统输送作为缺血性卒中中潜在的BBB稳定治疗。阐明 OA-NO2介导的BBB稳定和恢复的分子机制可能使我们发现新的 有效治疗缺血性中风的药物方法。