Oxyradical stress increases the biosynthesis of 2-arachidonoylglycerol: involvement of NADPH oxidase
文献类型: 外文期刊
作者: Matthews, Anberitha T. 1 ; Lee, Jung Hwa 1 ; Borazjani, Abdolsamad 1 ; Mangum, Lee C. 1 ; Hou, Xiang 1 ; Ross, Matt 1 ;
作者机构: 1.Mississippi State Univ, Coll Vet Med, Dept Basic Sci, Ctr Environm Hlth Sci, Mississippi State, MS 39762 USA
2.Jiangsu Acad Agr Sci, Inst Food Safety, Nanjing, Jiangsu, Peoples R China
关键词: 2-arachidonoylglycerol;macrophages;NADPH oxidase;atherosclerosis;endocannabinoids
期刊名称:AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY ( 影响因子:4.249; 五年影响因子:4.627 )
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收录情况: SCI
摘要: NADPH oxidase (Nox)-derived oxyradicals contribute to atherosclerosis by oxidizing low-density lipoproteins (LDL), leading to their phagocytosis by vascular macrophages. Endocannabinoids, such as 2-arachidonoylglycerol (2-AG), might be an important link between oxidative stress and atherosclerosis. We hypothesized that 2-AG biosynthesis in macrophages is enhanced following ligation of oxidized LDL by scavenger receptors via a signal transduction pathway involving Nox-derived ROS that activates diacylglycerol lipase-beta (DAGL-beta), the 2-AG biosynthetic enzyme. To test this idea, we challenged macrophage cell lines and murine primary macrophages with a xanthine oxidase system or with nonphysiological and physiological Nox stimulants [phorbol 12-my-ristate 13-acetate (PMA) and arachidonic acid (AA)]. Each stressor increased cellular superoxide levels and enhanced 2-AG biosynthetic activity in a Nox-dependent manner. Levels of cytosolic phospho-lipase A_2-dependent AA metabolites (eicosanoids) in primary macrophages were also dependent on Nox-mediated ROS. In addition, 2-AG levels in DAGL-beta-overexpressing COS7 cells were attenuated by inhibitors of Nox and DAGL-beta. Furthermore, ROS induced by men-adione (a redox cycling agent) or PMA could be partially attenuated by the cannabinoid 1/2 receptor agonist (WIN 55,212-2). Finally, cells that overexpress Nox2 components (Phox-COS7) synthesized larger amounts of 2-AG compared with the parental COS7 cells. Together, the results suggest a positive correlation between heightened oxygen radical flux and 2-AG biosynthesis in macrophage cell lines and primary macrophages. Because of the antioxidant and anti-inflammatory effects associated with 2-AG, the increased levels of this bioae-tive lipid might be an adaptive response to oxidative stress. Thus oxyradical stress may be counteracted by the enhanced endocannabi-noid tone.
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