Background and significance

Adaptation to changes in the ambient O2 tension is essentially required for the adaequate energy supply of humans and all other aerobic living organisms. Disturbances in the O2 and nutrient supply will have profound effects on not only cellular but also whole body function and may contribute to the development of various diseases like cancer, liver fibrosis, diabetes mellitus, the metabolic syndrome, artherosclerosis and thrombosis as well as pulmonary hypertension. These pathologies are also associated with high expression levels of plasminogen activator inhibitor-1 (PAI-1) indicating a bad prognosis, especially in breast cancer patients. We have shown that oxygen gradients, e.g. the periportal to perivenous drop of oxygen within the liver acinus, modulate the transcription of key regulatory genes. Thereby, we have demonstrated that hypoxia and insulin activate PAI-1 transcription via a transcriptional complex consisting of at least hypoxia-inducible factor-1alpha(HIF-alpha ).

In addition, a number of reports including our own have shown that HIFs also respond to growth and coagulation factors, hormones, cytokines and stress factors under non-hypoxic conditions by using reactive oxygen species (ROS) as mediators. Although these data show that ROS levels have an impact on HIF-alpha levels, there are diverse opinions about the enzymes and cellular compartments participating in ROS generation. Thus, different cellular compartments like the endoplasmic reticulum, the Golgi complex or the mitochondria may have a different role in redox signalling.

 

Viimeksi päivitetty: 28.10.2016