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(Circulation Research. 2007;100:7.)
© 2007 American Heart Association, Inc.

Editorials

Shooting the Messenger

Oxidative Stress Regulates Sphingosine-1-Phosphate

Michael Maceyka, Sheldon Milstien, Sarah Spiegel

From the Department of Biochemistry (M.M., S.S.), Virginia Commonwealth University School of Medicine, Richmond; Laboratory of Cellular and Molecular Regulation (S.M.), NIMH, NIH, Bethesda, Md.

Correspondence to Sarah Spiegel, Department of Biochemistry, Virginia Commonwealth University School of Medicine, 1101 E. Marshall St., Richmond, VA 23298-0614. E-mail sspiegel@vcu.edu

Key Words: sphingosine-1-phosphate • reactive oxygen species • monoamine oxidase • ceramide • apoptosis

An extract of the first 250 words of the full text is provided, because this article has no abstract.

Ischemia reduces oxygen availability (hypoxia) and can thus lead to tissue damage. However, restoration of blood flow, or reperfusion, has been shown initiate a second phase of injury. Ischemia/reperfusion (I/R) injury has been linked to the generation of reactive oxygen species (ROS), which in turn lead to tissue damage through induction of apoptosis.¹ Indeed, I/R injury is reduced by the administration of antioxidants. In addition to nonspecific targets such as lipids and DNA, ROS are becoming appreciated as second messengers involved in many intracellular signaling pathways.¹ Still, many of the pathways of ROS-dependent signaling remain to be elucidated.

ROS signaling may be mediated in part through sphingolipid metabolites. Sphingolipids are ubiquitous components of the lipid bilayer of eukaryotic cells consisting of a head group attached to ceramide. Ceramide is synthesized de novo or formed by the degradation of sphingolipids, such as sphingomyelin. Ceramide can be further deacylated to sphingosine which can then be phosphorylated by sphingosine kinases (SphK), forming sphingosine-1-phosphate (S1P). Ceramide and S1P are both potent signaling molecules with opposing biological effects. Ceramide is an important regulatory component of stress responses, typically inducing growth arrest and apoptosis.² In contrast, S1P promotes cell proliferation and survival.^3,4 Whereas stresses activate sphingomyelinases, producing ceramide leading to apoptosis, survival factors activate SphK1, resulting in accumulation of S1P and consequent suppression of ceramide-mediated apoptosis.^4,5 It has been suggested that the dynamic balance between intracellular S1P and ceramide, the "sphingolipid rheostat (sphingostat)", and the consequent regulation of opposing signaling pathways, are important factors determining cell . . . [Full Text of this Article]