Crucial processes for vascular homeostasis that are regulated by endothelial cells are their protection against apoptosis, adhesion of inflammatory cells and the ability to migrate into wounds. Over the last years it has become clear that these processes require intact and active mitochondria in endothelial cells. A role for NF-E2-Related Factor 2 (NRF2) and Thioredoxin-1 (TXN) in mitochondrial functions has been suggested by the fact that TXN stimulates the transcriptional activity of NRF2 in the cardiovascular system leading to upregulation of mitochondrial proteins related to oxidative phosphorylation and tricarboxylic acid (TCA) cycle. Moreover, novel NRF2 target genes were obtained, such as the genes for Nuclear Respiratory Factor 1 or Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1alpha, which are essential for mitochondrial biogenesis and functions. Thus, NRF2 and TXN seem to be important for counteracting mitochondrial dysfunction in the cardiovascular system.
Given the close relationship of TXN and NRF2 the common aims of this collaborative research project between the Leitinger laboratory, University of Virginia, Charlottesville, Virginia, USA and the Haendeler laboratory are:
(1) to determine the mechanisms of regulation of TXN/NRF2 interaction in endothelial cells, macrophages and dendritic cells and
(2) to elucidate the functional consequences of this interaction with a specific focus on mitochondrial functions, redox regulation and ensuing inflammatory reactions.
- Gonnissen, S.*, Ptok, J.*, Goy, C., Jander, K., Jakobs, P., Eckermann, O., Kaisers, W., von Ameln, F., Timm, J., Ale-Agha, N., Haendeler, J.**, Schaal, H.**, and Altschmied, J.** (2019). High Concentration of Low-Density Lipoprotein Results in Disturbances in Mitochondrial Transcription and Functionality in Endothelial Cells. Oxid Med Cell Longev 2019
- Dyballa-Rukes, N.*, Jakobs, P.*, Eckers, A.*, Ale-Agha, N., Serbulea, V., Aufenvenne, K., Zschauer, T.C., Rabanter, L.L., Jakob, S., von Ameln, F., Eckermann, O., Leitinger, N., Goy, C., Altschmied, J., Haendeler, J. (2017) The anti-apoptotic properties of APEX1 in the endothelium require the first twenty amino acids and converge on Thioredoxin-1. Antioxid Redox Signal. 26, 616-629.
- Jakobs, P.*, Serbulea, V.*, Leitinger, N., Eckers, A., Haendeler, J. (2017) Nuclear factor (erythroid-derived 2)-like 2 and Thioredoxin-1 in atherosclerosis and ischemia/reperfusion injury in the heart. Antioxid Redox Signal. 26, 630-644.
- Goy, C.#, Czypiorski, P.#, Altschmied, J.#, Jakob, S., Rabanter, L.L., Brewer, A.C., Ale-Agha, N., Dyballa-Rukes, N., Shah, A.M., Haendeler, J. (2014) The imbalanced redox status in senescent endothelial cells is due to dysregulated Thioredoxin-1 and NADPH oxidase 4. Exp Gerontol. 56, 45-52 (# contributed equally).
- Zschauer, T.-C., Matsushima, S., Altschmied, J., Shao, D., Sadoshima, J., Haendeler, J. (2013) Interacting with Thioredoxin-1 – disease or no disease? Antioxid. Redox. Signal. 18, 1053-1062.
- Zschauer, T.-C., Kunze, K., Jakob, S., Haendeler, J.*#, Altschmied, J.# (2011) Oxidative stress induced degradation of Thioredoxin-1 and apoptosis is inhibited by Thioredoxin-1/actin interaction in endothelial cells. Arterioscler. Thromb. Vasc. Biol., 31, 650-656.