Project 2

Protective role of Thioredoxin - 1 and its interaction partners in cardiovascular disorders

 

Background: Thioredoxin-1 (TXN) is one of the most important redox regulators in the cardiovascular system. TXN deficiency is embryonic lethal and an efficient knockdown (>90 %) of TXN in primary endothelial cells results in complete cell death within 24 hours, demonstrating the importance of TXN for vascular cells. Besides its well-described function as an antioxidant, it can also directly interact with proteins and thereby regulate their functions. Under conditions of oxidative stress and in the context of inflammation it is believed that TXN activity is dependent on the transcription factor nuclear factor E2-related factor 2 (NRF2), which regulates TXN reductase expression. Moreover, TXN has been demonstrated to directly interact with NRF2 and thereby regulates nuclear im- and/or export of NRF2. However, neither the upstream regulation of TXN as well as of NRF2 in the cardiovascular system is completely understood nor are their interaction partners fully discovered. 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 NRF2 and TXN in mitochondrial functions has been suggested (Koenitzer and Freeman, 2010) 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 nuclear respiratory factor 1, mitochondrial transcription factor 1, and peroxisome proliferator-activated receptor gamma co activator 1a, which are all essential for mitochondrial biogenesis and functions. Thus, NRF2 and TXN seem to be important for counteracting mitochondrial dysfunction in the cardiovascular system.

Previous work: The Haendeler lab has a long lasting experience in the investigation of TXN in endothelial cells. They discovered that TXN is required for the maintenance of sufficient levels of available nitric oxide (NO) in endothelial cells (Haendeler et al., 2002). Several studies were undertaken by the Haendeler laboratory to understand the control of the redox status in endothelial cells, which is important for the regulation of the activity of many transcription factors. They demonstrated that TXN is required for stabilizing the redox status, regulating transcription factor activity and thereby inhibiting apoptosis and promoting migration. Recently, they showed that TXN-dependent inhibition of endothelial cell apoptosis in response to oxidative stress was associated with TXN-actin complex formation. Moreover, they demonstrated that migration of endothelial cells depends on intact mitochondria.
The Leitinger lab has long standing experience in the role of inflammatory processes with respect to cardiovascular diseases, especially atherosclerosis. They discovered several oxidized phospholipids that are concentrated within atherosclerotic lesions and contribute to the enhanced monocyte-endothelial interaction and progression of atherosclerotic plaque formation. Recently they demonstrated that NRF2 acts as a key regulator in the formation of a novel macrophage phenotype (Mox) that develops in response to oxidative tissue damage. Thus, local formation of ROS plays an important role in intraorgan communication with an impact on TXN/NRF2 regulation as a common target.

Aims: Given the close relationship of TXN and NRF2 the common aims of our collaborative project are to determine the mechanisms of regulation of TXN/NRF2 interaction in endothelial, macrophages and dendritic cells and to elucidate the functional consequences of this interaction with a specific focus on mitochondrial functions, redox regulation and ensuing inflammatory reactions. We will also investigate the regulation of TXN in NRF2-deficient endothelial and inflammatory cells in vitro and in NRF2-deficient mice in vivo. Moreover, we are aiming at identification of new nuclear interaction partners of TXN in endothelial and inflammatory cells and whether these interactions occur also in vivo.

Publications

Jakobs, P.*, Serbulea, V.*, Leitinger, N., Eckers, A., and 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
*equal contribution

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., and Haendeler, J. (2016) 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
*equal contribution

Zurek, M., Altschmied, J., Kohlgrüber, S., Ale-Agha, N., and Haendeler, J. (2016) Role of Telomerase in the Cardiovascular System. Genes 7, 29

Schuler, D., Sansone, R., Freudenberger, T., Rodriguez-Mateos, A., Weber, G., Momma, T. Y., Goy, C., Altschmied, J., Haendeler, J., Fischer, J. W., Kelm, M., and Heiss, C. (2014) Measurement of endothelium-dependent vasodilation in mice--brief report. Arterioscler Thromb Vasc Biol 34, 2651-2657

Goy, C., Czypiorski, P., Altschmied, J., Jakob, S., Rabanter, L. L., Brewer, A. C., Ale- Agha, N., Dyballa-Rukes, N., Shah, A. M., and 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

Czypiorski, P., Altschmied, J., Rabanter, L. L., Goy, C., Jakob, S., and Haendeler, J. (2014) Outfielders playing in the infield: functions of aging-associated "nuclear" proteins in the mitochondria. Curr Mol Med 14, 1247-1251

Czypiorski, P., Rabanter, L. L., Altschmied, J., and Haendeler, J. (2013) Redox balance in the aged endothelium. Z Gerontol Geriatr 46, 635-638

Principal Investigator HHU

Prof. Dr. rer. nat. Judith Haendeler

IUF - Leibniz Institute for Environmental Medicine
Heisenberg group- Environmentally-induced cardiovascular degeneration

Principal Investigator HHU

Prof. Dr. Norbert Leitinger

Department of Pharmacology
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