Reactive oxygen species (ROS)

Reactive oxygen species (ROS) are essential for the first line host defense. Besides this, ROS play an important role in intra- and intercellular signal transduction and serve as second messengers. To do so, ROS must be produced in a timely and specific manner, a task fulfilled by the family of NADPH oxidases (Nox). Seven NADPH oxidases have been described so far. Our goal is to identify specific molecular and physiological functions of the enzymes of the NADPH oxidase family.

Nox1 and Nox2 can be acutely activated following stimulation of the cells with cytokines or chemokines. Once activated, they produce superoxide anions, which may, if produced at hig level, result in hypertension, inflammation and endothelial dysfunction. On the other hand, Nox2 is required in vascular repair processes by promoting progenitor cell mobilization and proliferation. The way of how this is possible, is a transient inhibition of phosphatases resulting on prolonged activity of the signaling pathways.

Besides the name defining membrane bound subunit, Nox1 and Nox2 must complex with other subunits. Those subunits may play Nox-independent tasks as well, which is one of the field of our current scientific interest.

In contrast to Nox1 and 2, Nox4 is constitutively active and can be considered as mainly protective. As Nox4 directly produces H2O2, its activity controls cysteine residue-oxidation in proteins, thereby altering their activity and downstream signaling effects such as phosphorylation or intracellular trafficking. The relatively small portion of ROS produced by this enzyme contributes to cellular homeostasis, especially in endothelial cells. Consequently, in mice the knockout of Nox4 results in a pronounced vascular inflammation and consequently in enhanced development of atherosclerosis and reduced angiogenesis. The constitutive maintenance of a low level of ROS by Nox4 implies its role not only in homeostasis but also in long lasting processes, such as differentiation. In fact, Nox4 promotes differentiation of adipocytes, osteoclasts and endothelial cells. Furthermore, Nox4 controls macrophage polarization by regulating the activity of NFκB, suggesting an anti-inflammatory role for Nox4. By maintaining cellular homeostasis and prevention of inflammation, Nox4 limits cancerogenic processes in multiple cells.

Team

Prof. Dr. Katrin Schröder

Fabian Hahner (Phd Student)

Tim Schader (Phd Student)

Manuela Spaeth (TA)

Christina Reschke (TA)