Sphingosine-1-phosphate: a novel nonhypoxic activator of hypoxia-inducible factor-1 in vascular cells
MD Michaud, GA Robitaille, JP Gratton… - … , and Vascular Biology, 2009 - Am Heart Assoc
MD Michaud, GA Robitaille, JP Gratton, DE Richard
Arteriosclerosis, Thrombosis, and Vascular Biology, 2009•Am Heart AssocObjective—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 …
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 …
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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