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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1347.)
© 2008 American Heart Association, Inc.

Cell Biology and Signaling

Nox4 and Nox2 NADPH Oxidases Mediate Distinct Cellular Redox Signaling Responses to Agonist Stimulation

Narayana Anilkumar; Roberta Weber; Min Zhang; Alison Brewer; Ajay M. Shah

From King’s College London British Heart Foundation Centre, Cardiovascular Division, The James Black Centre, London, UK.

Correspondence to Professor Ajay M. Shah, Department of Cardiology, The James Black Centre, King’s College London, 125 Coldharbour Lane, London SE5 9NU, UK. E-mail ajay.shah{at}kcl.ac.uk

Abstract

Objectives— The NADPH oxidase isoforms Nox2 and Nox4 are coexpressed in many cell types and are implicated in agonist-stimulated redox-sensitive signal transduction. We compared the involvement of Nox2 versus Nox4 in redox-sensitive protein kinase activation after agonist stimulation.

Methods and Results— We transfected HEK293 cells with Nox2 or Nox4 and compared ROS production and activation of mitogen activated protein kinases (MAPKs), Akt, and GSK3β after acute agonist stimulation. Nox4 overexpression substantially increased basal ROS generation whereas ROS generation in response to angiotensin II and tumor necrosis factor (TNF) was enhanced in Nox2-overexpressing cells. Nox4 overexpression induced basal activation of ERK1/2 and JNK whereas Nox2-transfected cells showed a modest increase in p38MAPK activation. After angiotensin II or TNF treatment, JNK activation was augmented in Nox2 but not Nox4-transfected cells, whereas insulin augmented phosphorylation of p38MAPK, Akt, and GSK3β specifically in Nox4-overexpressing cells and JNK specifically in Nox2-overexpressing cells.

Conclusions— These data indicate that Nox2 and Nox4 exhibit distinctive patterns of acute activation by angiotensin II, TNF, and insulin and regulate the activation of distinct protein kinases.

We compared the effects of Nox2 versus Nox4 overexpression in HEK293 cells. These isoforms had distinctive intracellular localization and exhibited isoform-specific ROS production and signaling responses to angiotensin II, TNF, or insulin. Nox2 and Nox4 may modulate distinct agonist-stimulated signaling pathways.

Key Words: NADPH oxidase • redox signaling • protein kinase • reactive oxygen species