Sphingosine-1-phosphate: a novel nonhypoxic activator of hypoxia-inducible factor-1 in vascular cells.
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.


RESULTS
We show that in vascular endothelial and smooth muscle cells, activation of the S1P type-2 receptor by S1P strongly increases HIF-1 alpha protein levels, the active subunit of HIF-1. This is achieved through pVHL-independent stabilization of HIF-1 alpha. 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.


CONCLUSIONS
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.
Michaud
Maude D
MD
Centre de Recherche du CHUQ, L'Hôtel-Dieu de Québec, Québec, Canada.
Robitaille
Geneviève A
GA
Gratton
Jean-Philippe
JP
Richard
Darren E
DE
D000818:Animals; D002417:Cattle; D015687:Cell Hypoxia; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D005786:Gene Expression Regulation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008246:Lysophospholipids / Q000378:metabolism*; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D055550:Protein Stability; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection
C497443:Hif1a protein, mouse; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008246:Lysophospholipids; D034741:RNA, Small Interfering; D049349:Receptors, Lysosphingolipid; C060506:sphingosine 1-phosphate; D013110:Sphingosine