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High Concentration of Antioxidants N-Acetylcysteine and Mitoquinone-Q Induces Intercellular Adhesion Molecule 1 and Oxidative Stress by Increasing Intracellular Glutathione¹

Tapan K. Mukherjee^2,*, Anurag K. Mishra, Srirupa Mukhopadhyay^* and John R. Hoidal^*

^* Department of Internal Medicine, Pulmonary Division, University of Utah Health Science Center, Salt Lake City, UT 84112; and Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555

In endothelial cells, the intracellular level of glutathione is depleted during offering protection against proinflammatory cytokine TNF--induced oxidative stress. Administration of anti-inflammatory drugs, i.e., N-acetylcysteine (NAC) or mitoquinone-Q (mito-Q) in low concentrations in the human pulmonary aortic endothelial cells offered protection against depletion of reduced glutathione and oxidative stress mediated by TNF-. However, this study addressed that administration of NAC or mito-Q in high concentrations resulted in a biphasic response by initiating an enhanced generation of both reduced glutathione and oxidized glutathione and enhanced production of reactive oxygen species, along with carbonylation and glutathionylation of the cellular proteins. This study further addressed that IB kinase (IKK), a phosphorylation-dependent regulator of NF-B, plays an important regulatory role in the TNF--mediated induction of the inflammatory cell surface molecule ICAM-1. Of the two catalytic subunits of IKK (IKK and IKK), low concentrations of NAC and mito-Q activated IKK activity, thereby inhibiting the downstream NF-B and ICAM-1 induction by TNF-. High concentrations of NAC and mito-Q instead caused glutathionylation of IKK, thereby inhibiting its activity that in turn enhanced the downstream NF-B activation and ICAM-1 expression by TNF-. Thus, establishing IKK as an anti-inflammatory molecule in endothelial cells is another focus of this study. This is the first report that describes a stressful situation in the endothelial cells created by excess of antioxidative and anti-inflammatory agents NAC and mito-Q, resulting in the generation of reactive oxygen species, carbonylation and glutathionylation of cellular proteins, inhibition of IKK activity, and up-regulation of ICAM-1expression.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant HL67281.

² Address correspondence and reprint requests to Dr. Tapan K Mukherjee, Department of Internal Medicine, Pulmonary Division, University of Utah Health Science Center, 26 North and 1900 East, Salt Lake City, UT 84112. E-mail address: tapan.mukherjee{at}hsc.utah.edu

³ Abbreviations used in this paper: GSH, reduced glutathione; IKK, IB kinase; ROS, reactive oxygen species; GSSG, oxidized GSH; NAC, N-acetylcysteine; mito-Q, mitoquinone; BSO, DL-buthionine-[S,R]-sulfoximine; GPx, glutathione peroxidase; GR, GSH reductase; G6PD, glucose-6-phosphate dehydrogenase; GCS, glutamylcysteine synthetase; HPAEC, human pulmonary aortic endothelial cell; HVA, homovanillic acid; DNPH, 2,4-dinitrophenylhydrazine; siRNA, small interfering RNA; Er, endoplasmic reticulum.

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