Limits...
Competitive HIF Prolyl Hydroxylase Inhibitors Show Protection against Oxidative Stress by a Mechanism Partially Dependent on Glycolysis.

Bergström AL, Fog K, Sager TN, Bruun AT, Thirstrup K - ISRN Neurosci (2013)

Bottom Line: In the present study, we compared competitive and noncompetitive HPH-inhibitor compounds in two different cell types (SH-SY5Y and PC12).Both competitive and non-competitive HPH inhibitors protected the cells against 6-OHDA induced oxidative stress.In addition, the protective effect of a specific HPH inhibitor was partially preserved when the cells were serum starved and exposed to 2-deoxyglucose, an inhibitor of glycolysis, indicating that other processes than restoring energy supply could be important for the HIF-mediated cytoprotection.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurodegeneration, Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.

ABSTRACT
The hypoxia inducible factor 1 (HIF-1) is a central transcription factor involved in the cellular and molecular adaptation to hypoxia and low glucose supply. The level of HIF-1 is to a large degree regulated by the HIF prolyl hydroxylase enzymes (HPHs) belonging to the Fe(II) and 2-oxoglutarate-dependent dioxygenase superfamily. In the present study, we compared competitive and noncompetitive HPH-inhibitor compounds in two different cell types (SH-SY5Y and PC12). Although the competitive HPH-inhibitor compounds were found to be pharmacologically more potent than the non-competitive compounds at inhibiting HPH2 and HPH1, this was not translated into the cellular effects of the compounds, where the non-competitive inhibitors were actually more potent than the competitive in stabilizing and translocatingHIF1 α to the nucleus (quantified with Cellomics ArrayScan technology). This could be explained by the high cellular concentrations of the cofactor 2-oxoglutarate (2-OG) as the competitive inhibitors act by binding to the 2-OG site of the HPH enzymes. Both competitive and non-competitive HPH inhibitors protected the cells against 6-OHDA induced oxidative stress. In addition, the protective effect of a specific HPH inhibitor was partially preserved when the cells were serum starved and exposed to 2-deoxyglucose, an inhibitor of glycolysis, indicating that other processes than restoring energy supply could be important for the HIF-mediated cytoprotection.

No MeSH data available.


Related in: MedlinePlus

HIF-1α stabilization and nuclear translocation in differentiated SHSH-5Y cells. The cells were treated with 10 or 25 μM FG41 for 3 hours, then fixed, and Hoechst-stained. The upper panel shows HIF-1α immunoreactivity alone and the lower panel shows the images merged with the Hoechst-staining.
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4061615&req=5

fig3: HIF-1α stabilization and nuclear translocation in differentiated SHSH-5Y cells. The cells were treated with 10 or 25 μM FG41 for 3 hours, then fixed, and Hoechst-stained. The upper panel shows HIF-1α immunoreactivity alone and the lower panel shows the images merged with the Hoechst-staining.

Mentions: FG41 treatment also resulted in HIF-1α stabilization and nuclear translocation in differentiated SH-SY5Y cells showing that the HIF-1α stabilization is not only a property of proliferative cells (Figure 3).


Competitive HIF Prolyl Hydroxylase Inhibitors Show Protection against Oxidative Stress by a Mechanism Partially Dependent on Glycolysis.

Bergström AL, Fog K, Sager TN, Bruun AT, Thirstrup K - ISRN Neurosci (2013)

HIF-1α stabilization and nuclear translocation in differentiated SHSH-5Y cells. The cells were treated with 10 or 25 μM FG41 for 3 hours, then fixed, and Hoechst-stained. The upper panel shows HIF-1α immunoreactivity alone and the lower panel shows the images merged with the Hoechst-staining.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4061615&req=5

fig3: HIF-1α stabilization and nuclear translocation in differentiated SHSH-5Y cells. The cells were treated with 10 or 25 μM FG41 for 3 hours, then fixed, and Hoechst-stained. The upper panel shows HIF-1α immunoreactivity alone and the lower panel shows the images merged with the Hoechst-staining.
Mentions: FG41 treatment also resulted in HIF-1α stabilization and nuclear translocation in differentiated SH-SY5Y cells showing that the HIF-1α stabilization is not only a property of proliferative cells (Figure 3).

Bottom Line: In the present study, we compared competitive and noncompetitive HPH-inhibitor compounds in two different cell types (SH-SY5Y and PC12).Both competitive and non-competitive HPH inhibitors protected the cells against 6-OHDA induced oxidative stress.In addition, the protective effect of a specific HPH inhibitor was partially preserved when the cells were serum starved and exposed to 2-deoxyglucose, an inhibitor of glycolysis, indicating that other processes than restoring energy supply could be important for the HIF-mediated cytoprotection.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurodegeneration, Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.

ABSTRACT
The hypoxia inducible factor 1 (HIF-1) is a central transcription factor involved in the cellular and molecular adaptation to hypoxia and low glucose supply. The level of HIF-1 is to a large degree regulated by the HIF prolyl hydroxylase enzymes (HPHs) belonging to the Fe(II) and 2-oxoglutarate-dependent dioxygenase superfamily. In the present study, we compared competitive and noncompetitive HPH-inhibitor compounds in two different cell types (SH-SY5Y and PC12). Although the competitive HPH-inhibitor compounds were found to be pharmacologically more potent than the non-competitive compounds at inhibiting HPH2 and HPH1, this was not translated into the cellular effects of the compounds, where the non-competitive inhibitors were actually more potent than the competitive in stabilizing and translocatingHIF1 α to the nucleus (quantified with Cellomics ArrayScan technology). This could be explained by the high cellular concentrations of the cofactor 2-oxoglutarate (2-OG) as the competitive inhibitors act by binding to the 2-OG site of the HPH enzymes. Both competitive and non-competitive HPH inhibitors protected the cells against 6-OHDA induced oxidative stress. In addition, the protective effect of a specific HPH inhibitor was partially preserved when the cells were serum starved and exposed to 2-deoxyglucose, an inhibitor of glycolysis, indicating that other processes than restoring energy supply could be important for the HIF-mediated cytoprotection.

No MeSH data available.


Related in: MedlinePlus