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Modulation of Hypoxia Induction Factor‐1 in Age Related Diseases
Author(s) -
Floyd Robert A,
Guo WeiXing,
Foster Steven Bradley
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1001-c
Subject(s) - hypoxia (environmental) , angiogenesis , erythropoiesis , hypoxia inducible factors , cancer research , biology , medicine , endocrinology , chemistry , gene , biochemistry , oxygen , organic chemistry , anemia
Hypoxia Induction Factor (HIF‐1) activity is important in anoxia/hypoxia events in aging and age‐related diseases. The HIF‐1 transcribes genes that play an important role in angiogenesis, vascular remodeling, glucose metabolism, cell proliferation and survival, as well as erythropoiesis and iron homeostasis that are important in tumor growth and the damage that occurs from heart attacks and stroke. Hepatocellular carcinoma development (HCC) in animal models is inhibited by α‐phenyl‐tert‐butyl nitrone (PBN). The mechanism of action of PBN is unknown. We observed that PBN inhibits both IGF‐1 as well as hypoxia‐mediated expression of HIF‐1α, as well as the HIF‐1 downstream gene iNOS in several cancer cell models. Cancer cell killing is increased in the presence of PBN when the cells are given a hypoxia/anoxia challenge. This implicates that PBN inhibits the expression of HIF‐1 downstream genes important in glycolysis and cell survival. Extending our efforts into stroke where PBN has shown significant effect in preventing brain injury. We explored the possibility that specific brain regions other than the cerebral cortex may be highly vulnerable to stroke. Pertinent to striatum, the dopaminergic PC‐12 cells exposed to anoxia/hypoxia caused an increase in HIF‐1α whereas IGF‐1 caused a decrease under normoxia as well as anoxia/hypoxia. Supported by NIH R01CA82506 and OCAST/OARS AR052‐041.