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Nitroalkene-Mediated Vascular Protection and Ischemic Stroke

硝基烯烃介导的血管保护和缺血性中风

基本信息

批准号：
8693028
负责人：
YUQING Eugene CHEN
金额：
$ 33.68万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
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/8693028
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

项目摘要

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(申请人提供)：缺血性中风是由一过性或永久性的局部脑血流减少引起的，以一系列细胞紊乱为特征。在美国，中风的死亡率为30%，是第三大死亡原因和成人残疾的主要原因。不幸的是，脑缺血后不可逆性脑损伤的迅速发展严重限制了有效治疗方法的发展。近年来，越来越多的研究表明，过氧化物酶体增殖物激活受体-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制中的两个重要介质。硝酸油酸(OA-NO2)和亚油酸(LNO2)是在一氧化氮(NO)依赖的氧化反应中形成的两种硝基烯类化合物，在人体血浆中被发现，被认为在多种细胞类型中调节生理功能。有意义的是，我们已经证明了OA-NO2和LNO2都是内源性PPAR3配体。此外，我们的初步研究首次证明，在大脑中动脉(MCA)闭塞24小时后，脑室内注射OA-NO2可以减少小鼠的脑梗塞体积和水肿。此外，我们还发现，在血管平滑肌细胞(VSMCs)中，OA-NO2可以与AT1R结合并抑制其信号转导。此外，我们还发现，OA-NO2可以抑制缺氧缺糖(OGD)后脑VSMCs和脑血管内皮细胞(CECs)的炎症反应。这些发现表明，硝基烯类化合物在缺血性脑损伤中起着关键的保护作用。在这个提案中，我们将检验中心假设，即硝酸烯(例如，OA-NO2)可能通过抑制AT1R信号通路和激活依赖PPAR3的级联反应来抑制脑缺血诱导的血管炎症，从而发挥神经元保护作用。具体地说，我们将确定1)通过AT1R和PPAR3信号通路抑制OGD诱导的脑血管细胞炎症；2)血管选择性激活PPAR3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信号有助于OA-NO2在缺血性中风中的神经元保护作用。阐明OA-NO2介导的脑缺血保护机制将有助于更好地了解硝基烯类化合物在缺血性卒中中的内源性信号转导作用，并将为合理设计和开发治疗卒中的硝基烯衍生物奠定坚实的基础。