Revised: March 25, 2013
Accepted: March 28, 2013
Published online: April 26, 2013
The sphingolipid metabolites ceramide, sphingosine, and sphingosine-1-phosphate (S1P) and its enzyme sphingosine kinase (SphK) play an important role in the regulation of cell proliferation, survival, inflammation, and cell death. Ceramide and sphingosine usually inhibit proliferation and promote apoptosis, while its metabolite S1P phosphorylated by SphK stimulates growth and suppresses apoptosis. Because these metabolites are interconvertible, it has been proposed that it is not the absolute amounts of these metabolites but rather their relative levels that determine cell fate. The relevance of this “sphingolipid rheostat” and its role in regulating cell fate has been borne out by work in many labs using many different cell types and experimental manipulations. A central finding of these studies is that SphK is a critical regulator of the sphingolipid rheostat, as it not only produces the pro-growth, anti-apoptotic messenger S1P, but also decreases levels of pro-apoptotic ceramide and sphingosine. Activation of bioactive sphingolipid S1P signaling has emerged as a critical protective pathway in response to acute ischemic injury in both cardiac and cerebrovascular disease, and these observations have considerable relevance for future potential therapeutic targets.
Core tip: The sphingolipid pathway has received considerable attention recently, because its active metabolites appear to have salutary effects on cytoprotection in experimental cardiac and cerebral ischemia. Both inhibitors and antagonists of the sphingolipid sphingosine-1-phosphate (S1P) pathway appear to limit ischemic injury through a variety of mechanisms. Because of the clinical availability of Fingolimod (FTY720), a S1P analog, for use in multiple sclerosis, preclinical and clinical studies should focus on the development of this and similar pharmaceuticals for a new indication.