Redox-sensitive regulation of the HIF pathway under non-hypoxic conditions in pulmonary artery smooth muscle cells
| Autor: | Agnes Görlach, Thomas Kietzmann, Daniela Flügel, Steve Bonello, Rachida S. BelAiba, John Hess, Talija Djordjevic |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
medicine.medical_specialty
Clinical Biochemistry Pulmonary Artery medicine.disease_cause Biochemistry Muscle Smooth Vascular Cell Line Superoxide dismutase chemistry.chemical_compound Mice Thrombin Internal medicine medicine Animals Humans Molecular Biology chemistry.chemical_classification Reactive oxygen species biology Glutathione peroxidase Cobalt Hypoxia (medical) Hypoxia-Inducible Factor 1 alpha Subunit Vascular endothelial growth factor Endocrinology chemistry Catalase biology.protein medicine.symptom Reactive Oxygen Species Oxidation-Reduction Oxidative stress medicine.drug Transcription Factors |
| Zdroj: | Biological chemistry. 385(3-4) |
| ISSN: | 1431-6730 |
| Popis: | Pulmonary hypertension and vascular remodeling processes are associated with oxidative stress, hypoxia and enhanced levels of thrombin and vascular endothelial growth factor (VEGF). The hypoxia-inducible transcription factor HIF regulates the expression of VEGF under hypoxia. The HIF pathway is also activated by thrombin or CoCl2, likely via reactive oxygen species (ROS). In this study we investigated whether the redox-modifying enzymes superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase affect HIF levels and the expression of VEGF mRNA in pulmonary artery smooth muscle cells (PASMC). Stimulation of PASMC with thrombin or CoCl2 increased ROS production and enhanced HIF-alpha protein and VEGF mRNA levels as well as HIF-dependent reporter gene activity. These responses were inhibited by vitamin C and by overexpression of GPX and catalase, whereas the opposite effects were observed in SOD-expressing cells. These findings suggest that an 'antioxidant' state with reduced levels of H2O2 limits the activation of the HIF pathway, whereas a 'prooxidant' state allowing elevated H2O2 levels promotes it. Thus, shifting the redox balance to a more reduced environment, thereby limiting VEGF expression, may be beneficial for treating remodeling processes during pulmonary hypertension. |
| Databáze: | OpenAIRE |
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