2.12. Transcription factor Nrf2 mediated gene regulation and signaling in the endothelium

Public examination of a doctoral dissertation in the field of Molecular Medicine

Doctoral candidate: MSc, BMed Henna-Kaisa Jyrkkänen

Time and venue: 2.12.2011 at 12 noon, Mediteknia Auditorium, Kuopio Campus

Language of the public examination: Finnish

Endothelial dysfunction plays a significant role in the development of atherosclerosis. Production of reactive oxygen species (ROS) is increased upon pathological conditions in the vascular wall and leads to the endothelial dysfunction. ROS are metabolized by antioxidant and detoxification enzymes regulated by Nuclear factor E2- Related Factor 2 (Nrf2). Nrf2 regulates gene expression via an antioxidant response element (ARE) that is conserved in the regulatory regions of target genes. Under physiological conditions, Nrf2 is regulated by Kelch-like ECH-associated protein 1 (Keap1), which mediates its degradation. Upon exposure to ROS, Nrf2 translocates to the nucleus and drives target gene expression. The aim of this thesis was to study regulatory mechanisms by which Nrf2 is activated in endothelial cells. Also, the mechanism by which Nrf2 mediated expression is silenced after induction and the potential role of Nrf2 as a negative regulator of gene expression were studied.         

Oxidized 1-palmitoyl-2-arachidonyl-sn-glycero3-phosphocholine (oxPAPC) is a phospholipid present in atherosclerotic lesions. In this thesis we show that oxPAPC activates Nrf2 and target gene expression in human endothelial cells and murine carotid arteries, contributing to the anti-inflammatory effects of oxPAPC. Nrf2 activation is also induced by nitro-oleic acid (OA-NO2) that is endogenously present in the circulation and its production is increased during cardiac ischemia-reperfusion injury. Here it is also shown that OA-NO2 activates another protective signaling pathway, heat shock response. BTB and CNC homology 1 (BACH1) is a repressive transcription factor that binds to the same ARE sequence as Nrf2. The functional ARE was identified from the BACH1 promoter as it mediates the inducible expression of the BACH1 gene in an Nrf2 dependent manner. These findings suggest a novel negative feedback mechanism by which Nrf2 reduces its own activity. To determine the endothelial specific target genes of Nrf2, we studied gene expression genome-wide and found that Nrf2 over-expression leads to the down-regulation of thioredoxin interacting protein (TXNIP), an inhibitor of thioredoxin. We also showed that Nrf2 reduces TXNIP promoter activity and expression of both TXNIP mRNA and protein levels.

In conclusion, Nrf2 is activated by endogenous activators leading to the increased expression of the protective genes and inhibition of inflammatory pathway. These results support the role of Nrf2 in the protection of the endothelium due to its antiatherogenic features.

The doctoral dissertation of Master of Science, Bachelor of Medicine Henna-Kaisa Jyrkkänen, entitled Transcription factor Nrf2 mediated gene regulation and signaling in the endothelium will be examined at the Faculty of Health Sciences. The opponent in the public examination will be Professor Sohvi Hörkkö of the University of Oulu and the custos will be Professor Anna-Liisa Levonen of the University of Eastern Finland.

Photo available for download at http://www.uef.fi/vaitoskuva t

For further information, please contact: Henna-Kaisa Jyrkkänen, p. 040 355 3580, henna-kaisa.jyrkkanen (at) uef.fi

Publishing year: 2011

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