Alcohol-LPP3 axis in ischemic stroke

项目摘要 酒精中毒的并发症，如中风和心肌病，是成年人死亡的主要原因。这个 这些事件的基本病理生理学涉及易感动脉内的脂类导致随后的 局限性炎症和血管功能障碍。而生物活性甘油磷脂溶血磷脂酸 在动脉粥样硬化性疾病中起着众所周知的作用，但它在酒精介导的脑功能障碍中的作用仍然存在 几乎没有被开发过。溶血磷脂酸的产生涉及溶血磷脂酰胆碱的水解。 分泌酶自体趋化蛋白，而磷脂磷酸酶-3(LPP3)催化溶血磷脂酸 去磷酸化以产生不具有受体活性的脂类产物。在本应用程序中，我们提供了第一个 大量饮酒(HAC)可提高脑血管自体趋化素水平并降低 LPP3的表达，这与溶血磷脂酸信号的增加有关。在HAC上，反应性 脑血管中的氧物种(ROS)增加，而氧化还原敏感的转录因子 NFAT(一种激活的T细胞的核因子)已被证明与自体趋化蛋白启动子结合并诱导其 表情。同样，氧化应激可能通过减少LPP3而耗尽HAc中的LPP3水平 表达或增强LPP3降解。因此，我们假设HAC改变了自体趋化蛋白和LPP3 通过产生ROS来驱动溶血磷脂酸信号转导和脑血管功能障碍。 以下相互关联的具体目标旨在提供体外、体内、 在实验治疗学的环境中。具体目标1将评估ROS的产生在自体分类中的作用 HAC后脑血管中溶血磷脂酸的表达和产生。特定目标2将 确定ROS产生在LPP3耗竭和LPA产生在以下脑血管系统中的作用 HAC。我们可以确定细胞与线粒体抗氧化状态的调节是否会赋予 HAC后的差别化保护作用。我们的结果应该会提供对信号系统的具体洞察 HAc介导，可能为治疗提供新的靶点，并可能改善脑血管疾病。

Project Abstract Complications of alcoholism such as stroke and cardiomyopathy are leading causes of death among adults. The underlying pathophysiology of these events involves lipids within susceptible arteries leading to subsequent localized inflammation and vascular dysfunction. While the bioactive glycerophospholipid lysophosphatidic acid plays a well-known role in atherosclerotic disease, its role in alcohol-mediated cerebral dysfunction remains virtually unexplored. Lysophosphatidic acid production involves hydrolysis of lysophosphatidylcholine by the secreted enzyme autotaxin, whereas lipid phosphate phosphatase-3 (LPP3) catalyzes lysophosphatidic acid dephosphorylation to generate lipid products that are not receptor active. In this application, we present the first evidence that heavy alcohol consumption (HAC) enhances the cerebrovascular autotaxin levels and decreases LPP3 expression, and this is associated with increased lysophosphatidic acid signaling. Upon HAC, reactive oxygen species (ROS) increases in the cerebrovasculature, whereas the redox-sensitive transcription factor NFAT (a nuclear factor of activated T-cells) has been shown to bind to the autotaxin promoter and induce its expression. Similarly, oxidant stress may deplete LPP3 levels in the context of HAC through reduced LPP3 expression or enhanced LPP3 degradation. Thus, we hypothesize that HAC alters autotaxin and LPP3 expression through ROS production to drive lysophosphatidic acid signaling and cerebrovascular dysfunction. The following interrelated specific aims are designed to provide step-wise and in-depth studies in vitro, in vivo, and in experimental therapeutics settings. Specific aim 1 will assess the role of ROS production in autotaxin expression and lysophosphatidic acid production in the cerebrovasculature following HAC. Specific aim 2 will determine the role of ROS production in LPP3 depletion and LPA production in the cerebrovasculature following HAC. We could identify whether modulation of cellular versus mitochondrial antioxidant status confers a differential protective effect following HAC. Our results should provide specific insight into signaling systems mediated by HAC and may provide novel targets for treatment and might improve cerebrovascular disorders.