Oxyradical stress increases the biosynthesis of 2-arachidonoylglycerol

Involvement of NADPH oxidase

Anberitha Matthews, Jung Hwa Lee, Abdolsamad Borazjani, Lee C. Mangum, Xiang Hou, Matthew K. Ross

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

NADPH oxidase (Nox)derived oxyradicals contribute to atherosclerosis by oxidizing lowdensity lipoproteins (LDL), leading to their phagocytosis by vascular macrophages. Endocannabinoids, such as 2-arachidonoylglycerol (2AG), 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.

Original languageEnglish (US)
Pages (from-to)C960-C974
JournalAmerican Journal of Physiology - Cell Physiology
Volume311
Issue number6
DOIs
StatePublished - Dec 12 2016

Fingerprint

NADPH Oxidase
Macrophages
Lipoprotein Lipase
Endocannabinoids
Arachidonic Acid
Atherosclerosis
Acetates
Oxidative Stress
Cytosolic Phospholipases A2
Lipoprotein Receptors
Vitamin K 3
Scavenger Receptors
Cell Line
Eicosanoids
Cannabinoids
Xanthine Oxidase
2-arachidonylglycerol
Phagocytosis
Superoxides
Lipoproteins

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cell Biology

Cite this

Oxyradical stress increases the biosynthesis of 2-arachidonoylglycerol : Involvement of NADPH oxidase. / Matthews, Anberitha; Lee, Jung Hwa; Borazjani, Abdolsamad; Mangum, Lee C.; Hou, Xiang; Ross, Matthew K.

In: American Journal of Physiology - Cell Physiology, Vol. 311, No. 6, 12.12.2016, p. C960-C974.

Research output: Contribution to journalArticle

Matthews, Anberitha ; Lee, Jung Hwa ; Borazjani, Abdolsamad ; Mangum, Lee C. ; Hou, Xiang ; Ross, Matthew K. / Oxyradical stress increases the biosynthesis of 2-arachidonoylglycerol : Involvement of NADPH oxidase. In: American Journal of Physiology - Cell Physiology. 2016 ; Vol. 311, No. 6. pp. C960-C974.
@article{9fd56833e2ce4546931040e2e26b43ce,
title = "Oxyradical stress increases the biosynthesis of 2-arachidonoylglycerol: Involvement of NADPH oxidase",
abstract = "NADPH oxidase (Nox)derived oxyradicals contribute to atherosclerosis by oxidizing lowdensity lipoproteins (LDL), leading to their phagocytosis by vascular macrophages. Endocannabinoids, such as 2-arachidonoylglycerol (2AG), 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.",
author = "Anberitha Matthews and Lee, {Jung Hwa} and Abdolsamad Borazjani and Mangum, {Lee C.} and Xiang Hou and Ross, {Matthew K.}",
year = "2016",
month = "12",
day = "12",
doi = "10.1152/ajpcell.00251.2015",
language = "English (US)",
volume = "311",
pages = "C960--C974",
journal = "American Journal of Physiology",
issn = "0363-6143",
publisher = "American Physiological Society",
number = "6",

}

TY - JOUR

T1 - Oxyradical stress increases the biosynthesis of 2-arachidonoylglycerol

T2 - Involvement of NADPH oxidase

AU - Matthews, Anberitha

AU - Lee, Jung Hwa

AU - Borazjani, Abdolsamad

AU - Mangum, Lee C.

AU - Hou, Xiang

AU - Ross, Matthew K.

PY - 2016/12/12

Y1 - 2016/12/12

N2 - NADPH oxidase (Nox)derived oxyradicals contribute to atherosclerosis by oxidizing lowdensity lipoproteins (LDL), leading to their phagocytosis by vascular macrophages. Endocannabinoids, such as 2-arachidonoylglycerol (2AG), 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.

AB - NADPH oxidase (Nox)derived oxyradicals contribute to atherosclerosis by oxidizing lowdensity lipoproteins (LDL), leading to their phagocytosis by vascular macrophages. Endocannabinoids, such as 2-arachidonoylglycerol (2AG), 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.

UR - http://www.scopus.com/inward/record.url?scp=85006269808&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85006269808&partnerID=8YFLogxK

U2 - 10.1152/ajpcell.00251.2015

DO - 10.1152/ajpcell.00251.2015

M3 - Article

VL - 311

SP - C960-C974

JO - American Journal of Physiology

JF - American Journal of Physiology

SN - 0363-6143

IS - 6

ER -