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: 10293575
• 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/10293575
• 关键词: Adult; Affect; Age; Aging; Anti-Inflammatory Agents; Astrocytes; Attenuated; Blood - brain barrier anatomy; Blood Preservation; Blood Proteins; Brain; Brain Infarction; Brain Injuries; Cardiovascular system; Cause of Death; Cells; Cerebral Ischemia; Cerebrum; Coculture Techniques; Data; Development; Edema; Endothelial Cells; Event; Extravasation; Fatty Acids; Functional disorder; Genetic; Glucose; Hemorrhage; Human; Immune; Impairment; In Vitro; Infiltration; Inflammation; Inflammation Mediators; Inflammatory Response; Injury; Intravenous; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Lead; Ligands; Maintenance; Mediating; Mediator of activation protein; 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; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Physiological; Plasma; Play; Publications; Reaction; Recovery; Regulation; Reperfusion Injury; Reperfusion Therapy; Rodent; Role; Signal Pathway; Signal Transduction; Signaling Protein; Stroke; Survivors; Testing; Therapeutic; Therapeutic Intervention; Thrombolytic Therapy; Tight Junctions; Time; Tumor-infiltrating immune cells; United States; Veterans; base; blood-brain barrier disruption; brain endothelial cell; cell type; cerebrovascular; deprivation; disability; effective therapy; functional improvement; functional outcomes; genetic manipulation; improved; mRNA Expression; neurobehavior; neurobehavioral; neuron loss; neurovascular; neurovascular injury; nitroalkene; novel; 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面临的主要医疗问题之一。至少有 15,000 名退伍军人 每年都有人因中风住院，大多数幸存者都患有长期神经损伤。 不幸的是，有效疗法的开发受到严重限制。大量研究表明 BBB 崩溃会引发一系列毁灭性的事件，导致外周免疫的迁移 细胞、脑炎症反应、水肿、出血性转化、神经元损失和最终 脑缺血/再灌注（I/R）后的神经功能缺损。因此，有必要确定机制并 制定有效的治疗策略，保护血脑屏障完整性并防止永久性神经血管损伤 I/R 之后。 硝基油酸 (OA-NO2) 是一氧化氮 (NO) 依赖性氧化反应中形成的硝基烯烃，具有 在人体血浆中发现，被认为是调节生理调节的新型细胞信号传导介质 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- 激活受体-γ (PPARγ) 配体并在生理水平激活 PPARγ。最新数据表明 OA-NO2 显着减少外周血管炎症和腔内血管损伤。挑衅地， 一些出版物记录了 OA-NO2 在缺血再灌注条件下增加，并且 减轻心脏或肾脏缺血/再灌注损伤。然而，功能意义和分子 OA-NO2 调节脑血管发病机制的机制，特别是 BBB 破坏及其结果 缺血性卒中的神经系统结局尚未被探索。 在我们的初步研究中，我们最近首次发现静脉内 (i.v.) 给药 OA-NO2 可以减少 BBB 渗漏、缩小脑梗塞并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 显着提高 mRNA 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。 这些发现表明硝基烯烃可能在缺血性脑中发挥关键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，从而引起神经血管保护。此次活动将实现三个目标 提议。目标1：明确OA-NO2在缺血性中风后BBB功能障碍/恢复和脑损伤中的作用； 目标2：阐明OA-NO2调节中风后BBB功能障碍/恢复的机制；目标 3： 探索系统性递送 OA-NO2 作为缺血性中风的潜在 BBB 稳定疗法。阐明 OA-NO2 介导的 BBB 稳定和恢复的分子机制可能会引导我们发现新的 有效治疗缺血性中风的药物方法。