Abstract
Hypoxia-inducible factor 1 (HIF-1) is a critical mediator of physiological responses to acute and chronic hypoxia. First, HIF-1 is required for the development of the systems that mediate these responses, including the heart, blood and blood vessels. Mice with complete HIF-1α deficiency manifest developmental defects that involve all three components of the circulatory system. Second, HIF-1 mediates changes in gene expression that underlie physiological responses to chronic hypoxia, such as increased erythropoiesis and angiogenesis. Hif1a+/- mice, which are partially HIF-1α deficient, manifest impaired hypoxia-induced pulmonary vascular remodelling. Smooth muscle cells from pulmonary arteries (PASMCs) of wild-type mice subjected to chronic hypoxia manifest hypertrophy, depolarization, increased [Ca22+]i, and decreased voltage-gated K+ currents. These responses are impaired in PASMCs from Hif1a+/- mice. Carotid bodies isolated from Hif1a+/- mice are unresponsive to hypoxia despite normal histology and normal responses to cyanide stimulation. Rat PC12 cells share properties with O2-sensing glomus cells of the carotid body, including hypoxia-inducible expression of tyrosine hydroxylase, the rate limiting enzyme for catecholamine biosynthesis. In PC12 cells subjected to intermittent hypoxia, Ca2+/calmodulin-dependent kinase activity leads to HIF-1 transcriptional activity and tyrosine hydroxylase mRNA expression. Thus, HIF-1 regulates both acute and chronic responses to continuous and intermittent hypoxia.
Original language | English (US) |
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Title of host publication | Signalling Pathways in Acute Oxygen Sensing |
Publisher | wiley |
Pages | 2-14 |
Number of pages | 13 |
ISBN (Electronic) | 9780470035009 |
ISBN (Print) | 0470014571, 9780470014578 |
DOIs | |
State | Published - Oct 7 2008 |
Keywords
- HIF-1 gene regulation
- HIF-1 induced by intermittent hypoxia
- Hypoxia response element (HRE)
- Hypoxia-inducible factor 1 (HIF-1)
- Vascular endothelial growth factor (VEGF)
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology