Influence of H2S on the transcription factors HIF-1α and NF-κB in THP-1 macrophages

Lilian Lohninger
2013 unpublished
In mammalian cells, the transcription factor HIF-1 is essential for the regulation of oxy-gen supply. HIF-1 is a heterodimer composed of the O2-dependent HIF-1α subunit and the constitutively expressed HIF-1β subunit. Hypoxia results in an excessive upregula-tion of HIF-1α protein expression, whereas it is abolished under normal oxygen supply due to proteosomal degradation. There are also several stimuli which stabilize HIF-1α under normoxic conditions, e.g. specific growth factors, ROS and
more » ... ogen species. Throughout our investigations we could confirm the increasing effect of hypoxia on the HIF-1α expression. Currently, little is known about the function of H2S in the physiological system. Even, if H2S has protective or damaging effects on living organisms is unclear to date. Thus, we aimed to get further insights into the meaning of hydrogen sulfides. Budde and Roth constituted that H2S increases HIF-1α in C. elegans. Acting on this assumption, our aim was to investigate whether H2S also enhances HIF-1α protein expression in THP-1 macrophages. Therefore we used a synthetic hydrogen sulfide donor, called GYY4137. In this analysis we could show that 1 mmol/l GYY4137 results in a significant enhance-ment of HIF-1α in THP-1 macrophages. The increasing effect of GYY4137, as H2S-releaser, on HIF-1α was exhibited by us for the first time. We also found that incubation of the cells with GYY4137 under hypoxic conditions re-sults in an even more increased HIF-1α signal. HIF-1α migrates into the nucleus when it is activated. In this study we could demonstrate that GYY4137 was able to increase HIF-1a protein expression in the nucleus in H2S treated macrophages. The pathway, by which H2S initiates the activation of HIF-1α, is by now not investigated. An important target protein of HIF-1α is the glucose transporter GLUT1, which mediates cellular glucose uptake. During our investigations we found that GYY4137 has a similar effect on GLUT1. Our evaluations showed that GLUT1 increases after H2S incubation and is even more en [...]
doi:10.25365/thesis.29192 fatcat:hxitceuwknfkrjsmoajwsw4gpa