Nrf2 activation supports cell survival during hypoxia and hypoxia/reoxygenation in cardiomyoblasts; the roles of reactive oxygen and nitrogen species

Kolamunne, Rajitha T., Dias, Irundika H.K., Vernallis, Ann B., Grant, Melissa M. and Griffiths, Helen R. (2013). Nrf2 activation supports cell survival during hypoxia and hypoxia/reoxygenation in cardiomyoblasts; the roles of reactive oxygen and nitrogen species. Redox biology, 1 (1), pp. 418-426.

Abstract

Adaptive mechanisms involving upregulation of cytoprotective genes under the control of transcription factors such as Nrf2 exist to protect cells from permanent damage and dysfunction under stress conditions. Here we explore of the hypothesis that Nrf2 activation by reactive oxygen and nitrogen species modulates cytotoxicity during hypoxia (H) with and without reoxygenation (H/R) in H9C2 cardiomyoblasts. Using MnTBap as a cell permeable superoxide dismutase (SOD) mimetic and peroxynitrite scavenger and L-NAME as an inhibitor of nitric oxide synthase (NOS), we have shown that MnTBap inhibited the cytotoxic effects of hypoxic stress with and without reoxygenation. However, L-NAME only afforded protection during H. Under reoxygenation, conditions, cytotoxicity was increased by the presence of L-NAME. Nrf2 activation was inhibited independently by MnTBap and L-NAME under H and H/R. The increased cytotoxicity and inhibition of Nrf2 activation by the presence of L-NAME during reoxygenation suggests that NOS activity plays an important role in cell survival at least in part via Nrf2-independent pathways. In contrast, O2 -• scavenging by MnTBap prevented both toxicity and Nrf2 activation during H and H/R implying that toxicity is largely dependent on O2 -.To confirm the importance of Nrf2 for myoblast metabolism, Nrf2 knockdown with siRNA reduced cell survival by 50% during 4h hypoxia with and without 2h of reoxygenation and although cellular glutathione (GSH) was depleted during H and H/R, GSH loss was not exacerbated by Nrf2 knockdown. These data support distinctive roles for ROS and RNS during H and H/R for Nrf2 induction which are important for survival independently of GSH salvage. © 2013 The Authors.

Publication DOI: https://doi.org/10.1016/j.redox.2013.08.002
Divisions: Life & Health Sciences > Biosciences
Life & Health Sciences
Life & Health Sciences > Applied Health Research Group
Additional Information: This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivativeWorksLicense, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.
Uncontrolled Keywords: adaptive,glutathione,L-NAME,MnTBap,RNS,ROS,Biochemistry,Organic Chemistry
Full Text Link:
Related URLs: http://www.scopus.com/inward/record.url?scp=84883776707&partnerID=8YFLogxK (Scopus URL)
Published Date: 2013
Authors: Kolamunne, Rajitha T.
Dias, Irundika H.K. ( 0000-0002-6620-8221)
Vernallis, Ann B.
Grant, Melissa M.
Griffiths, Helen R. ( 0000-0002-2666-2147)

Export / Share Citation


Statistics

Additional statistics for this record