P2: Protective role of Thioredoxin - 1 and its interaction partners in cardiovascular disorders
Background
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.
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 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 TXN and NRF2 with a specific focus on mitochondrial functions, redox regulation and ensuing inflammatory reactions.