Direct antioxidant properties of methotrexate: Inhibition of malondialdehyde-acetaldehyde-protein adduct formation and superoxide scavenging.

Authors

Matthew C. Zimmerman, University of Nebraska Medical CenterFollow
Dahn L. Clemens, University of Nebraska Medical CenterFollow
Michael J. Duryee, University of Nebraska Medical CenterFollow
Cleofes Sarmiento, University of Nebraska Medical CenterFollow
Andrew Chiou, University of Nebraska Medical CenterFollow
Carlos D. Hunter, University of Nebraska Medical CenterFollow
Jun Tian, University of Nebraska Medical CenterFollow
Lynell W. Klassen, University of Nebraska Medical CenterFollow
James R. O'Dell, University of Nebraska Medical CenterFollow
Geoffrey M. Thiele, University of Nebraska Medical CenterFollow
Ted R. Mikuls, University of Nebraska Medical CenterFollow
Daniel R. Anderson, University of Nebraska Medical CenterFollow

Document Type

Article

Journal Title

Redox Biology

Publication Date

10-2017

Volume

13

Abstract

Methotrexate (MTX) is an immunosuppressant commonly used for the treatment of autoimmune diseases. Recent observations have shown that patients treated with MTX also exhibit a reduced risk for the development of cardiovascular disease (CVD). Although MTX reduces systemic inflammation and tissue damage, the mechanisms by which MTX exerts these beneficial effects are not entirely known. We have previously demonstrated that protein adducts formed by the interaction of malondialdehyde (MDA) and acetaldehyde (AA), known as MAA-protein adducts, are present in diseased tissues of individuals with rheumatoid arthritis (RA) or CVD. In previously reported studies, MAA-adducts were shown to be highly immunogenic, supporting the concept that MAA-adducts not only serve as markers of oxidative stress but may have a direct role in the pathogenesis of inflammatory diseases. Because MAA-adducts are commonly detected in diseased tissues and are proposed to mitigate disease progression in both RA and CVD, we tested the hypothesis that MTX inhibits the generation of MAA-protein adducts by scavenging reactive oxygen species. Using a cell free system, we found that MTX reduces MAA-adduct formation by approximately 6-fold, and scavenges free radicals produced during MAA-adduct formation. Further investigation revealed that MTX directly scavenges superoxide, but not hydrogen peroxide. Additionally, using the Nrf2/ARE luciferase reporter cell line, which responds to intracellular redox changes, we observed that MTX inhibits the activation of Nrf2 in cells treated with MDA and AA. These studies define previously unrecognized mechanisms by which MTX can reduce inflammation and subsequent tissue damage, namely, scavenging free radicals, reducing oxidative stress, and inhibiting MAA-adduct formation.

DOI Link

10.1016/j.redox.2017.07.018

ISSN

2213-2317

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.

Recommended Citation

Zimmerman, Matthew C.; Clemens, Dahn L.; Duryee, Michael J.; Sarmiento, Cleofes; Chiou, Andrew; Hunter, Carlos D.; Tian, Jun; Klassen, Lynell W.; O'Dell, James R.; Thiele, Geoffrey M.; Mikuls, Ted R.; and Anderson, Daniel R., "Direct antioxidant properties of methotrexate: Inhibition of malondialdehyde-acetaldehyde-protein adduct formation and superoxide scavenging." (2017). Journal Articles: Cellular & Integrative Physiology. 27.
https://digitalcommons.unmc.edu/com_cell_articles/27