Sphingosine-1-Phosphate

• DOI: 10.1161/atvbaha.109.185280
• Publication Date: 2009-05-08T01:59:41Z
• Authors: Maude D. Michaud; Geneviève A. Rob...; Jean-Philippe Gra...; Darren E. Richard
• Keywords: 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

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.