Redox-sensitive regulation of the HIF pathway under non-hypoxic conditions in pulmonary artery smooth muscle cells.
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.
BelAiba
Rachida S
RS
Experimentelle Kinderkardiologie, Klinik für Kinder-Kardiologie und Angeborene Herzfehler, Deutsches Herzzentrum München an der Technischen Universität München, D-80636 München, Germany.
Djordjevic
Talija
T
Bonello
Steve
S
Flügel
Daniela
D
Hess
John
J
Kietzmann
Thomas
T
Görlach
Agnes
A
D000818:Animals; D002460:Cell Line; D003035:Cobalt / Q000494:pharmacology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism*
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D003035:Cobalt; D013917:Thrombin; C018021:cobaltous chloride