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
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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