Sphingosine-1-Phosphate
Cell Nucleus
0301 basic medicine
Time Factors
Protein Stability
Myocytes, Smooth Muscle
Endothelial Cells
Hypoxia-Inducible Factor 1, alpha Subunit
Cell Hypoxia
Muscle, Smooth, Vascular
Rats
3. Good health
Mice
Receptors, Lysosphingolipid
03 medical and health sciences
Gene Expression Regulation
Sphingosine
Animals
Cattle
RNA Interference
Lysophospholipids
RNA, Small Interfering
Rats, Wistar
Cells, Cultured
DOI:
10.1161/atvbaha.109.185280
Publication Date:
2009-05-08T01:59:41Z
AUTHORS (4)
ABSTRACT
Objective—
Sphingosine-1-phosphate (S1P) is a potent bioactive phospholipid responsible for a variety of vascular cell responses. Hypoxia-inducible factor-1 (HIF-1) is a transcriptional activator of genes essential for adaptation to low oxygen. S1P and HIF-1 are both important mediators of vascular cell responses such as migation, proliferation, and survival. Studies have shown that nonhypoxic stimuli can activate HIF-1 in oxygenated conditions. Here, we attempt to determine whether S1P can modulate the vascular activation of HIF-1.
Methods and Results—
We show that in vascular endothelial and smooth muscle cells, activation of the S1P type-2 receptor by S1P strongly increases HIF-1α protein levels, the active subunit of HIF-1. This is achieved through pVHL-independent stabilization of HIF-1α. We demonstrate that the HIF-1 nuclear complex, formed on S1P stimulation, is transcriptionally active and specifically binds to a hypoxia-responsive elements. Moreover, S1P activates the expression of genes known to be closely regulated by HIF-1.
Conclusion—
Our results identify S1P as a novel and potent nonhypoxic activator of HIF-1. We believe that understanding the role played by HIF-1 in S1P gene regulation will have a strong impact on different aspects of vascular biology.
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CITATIONS (54)
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