title: Oxyradical stress increases the biosynthesis of 2-arachidonoylglycerol: involvement of NADPH oxidase.
abstract: 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-β (DAGL-β), 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-myristate 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 phospholipase A2-dependent AA metabolites (eicosanoids) in primary macrophages were also dependent on Nox-mediated ROS. In addition, 2-AG levels in DAGL-β-overexpressing COS7 cells were attenuated by inhibitors of Nox and DAGL-β. Furthermore, ROS induced by menadione (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 bioactive lipid might be an adaptive response to oxidative stress. Thus oxyradical stress may be counteracted by the enhanced endocannabinoid tone.
authors: Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi; and.
authors: Anberitha T
authors: AT
authors: Matthews
authors: Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi; and.
authors: Jung Hwa
authors: JH
authors: Lee
authors: Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi; and.
authors: Abdolsamad
authors: A
authors: Borazjani
authors: Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi; and.
authors: Lee C
authors: LC
authors: Mangum
authors: Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi; and.|Institute of Food Safety, Jiangsu Academy of Agricultural Sciences, Nanjing, China.
authors: Xiang
authors: X
authors: Hou
authors: Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi; and mross@cvm.msstate.edu.
authors: Matthew K
authors: MK
authors: Ross
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001095:Arachidonic Acids / Q000378:metabolism*; D019556:COS Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D063388:Endocannabinoids / Q000378:metabolism*; D005989:Glycerides / Q000378:metabolism*; D018922:HL-60 Cells; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D019255:NADPH Oxidases / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D010587:Phagocytosis / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D005989:Glycerides; D008077:Lipoproteins, LDL; D017382:Reactive Oxygen Species; C099252:oxidized low density lipoprotein; D016718:Arachidonic Acid; C094503:glyceryl 2-arachidonate; D019255:NADPH Oxidases
keywords: 2-arachidonoylglycerol; NADPH oxidase; atherosclerosis; endocannabinoids; macrophages