Sphingosine 1Phosphate S1P

S1P came to prominence a few years after LPA and was found to mimic many of the biologic activities of LPA. A seminal study from the laboratory of Garcia [5] demonstrated that S1P decreases endothelial permeability across cell monolayers derived from bovine and human pulmonary arteries and human umbilical vein. In a number of cell types, S1P appears biologically to be much more potent than LPA. For example, S1P is more active than LPA in human umbilical vein endothelial cells with regard to the intracellular mobilization of calcium, cytoskeletal reorganization, and cell migration. In our hands, S1P increases the barrier function of endothelial cell monolayers derived from pulmonary arteries to an approximately twentyfold greater extent than does LPA.

S1P and LPA are the leading candidates for the soluble factor released from platelets that maintains the barrier function of the vascular endothelium. The plasma concentrations of S1P and LPA are 0.2 ||M and negligible, respectively, and the serum concentrations are 0.5 to 1.0 and 10 ||M, respectively. Both S1P and LPA are present in platelets and to a lesser extent in other cells such as leukocytes, fibroblasts, erythrocytes, and adipocytes and are released upon activation during blood coagulation, inflammation, tissue injury, and neoplasia. Platelets have the potential to synthesize and store S1P because platelets have an abundance of sphingosine kinase, which converts sphingosine to S1P, and relatively no lipases to degrade S1P. S1P and LPA bind to albumin on which they retain biological activity and are protected against hydrolysis by serum phospholipases. Cellular responses of S1P and LPA have been grouped into two categories: (1) growth-related activities such as proliferation, differentiation, and suppression of apoptosis; and (2) cytoskeletal functions such as shape change, aggregation, adhesion, chemotaxis, contraction, and secretion. Micromolar concentrations are required for growth-related functions and nanomolar concentrations stimulate cytoskeletal responses.

Although S1P has been proposed to be the major factor in PCM that imparts the barrier-enhancing property, no one has detected S1P in active conditioned medium. We attempted to identify the lipids in two batches of PCM and in the albumin immunoprecipitate from one of the batches of PCM by using electrospray mass spectrometry (Table I); all three samples were equally potent in enhancing endothe-lial electrical resistance. A number of lipids were identified, and there were 10 unknown lipids. Lipid profiles were almost identical between PCM and the methanol extract of the albumin immunoprecipitate, indicating the importance of albumin as a lipid-carrier. Interestingly, LPA was detected as a small peak of palmitoyl (16:0)-LPA only in one batch of conditioned medium. Palmitoyl-LPA, stearoyl-LPA, and arachidonoyl-LPA are the major molecular species of LPA produced from thrombin-stimulated platelets. Surprisingly, S1P was not present in any of the three samples tested.

Table I Electrospray Mass Spectrometry of Bligh & Dyer and Modified Folch Extracts of Platelet-Conditioned Medium.

Bligh & Dyer extraction

Folch extraction

Decanoic (10:0)

Octanoic (8:0)

Myristic (14:0)

Unknown

Pentadecanoic (15:0)

Unknown

Palmitic (16:0)

Myristic (14:0)

Linoleic (18:2)

Palmitoleic (16:1)

Oleic acid (18:1)

Palmitic (16:0)

Stearic (18:0)

Linolenic (18:3)

C18 sphingosine

Linoleic (18:2)

C18 sphingonine

Oleic (18:1)

Arachidonic (20:4)

Stearic (18:0)

Homogamma linolenic (20:3)

C18 dihydrosphingosine

Eicosadienoic (20:2)

C18 sphingosine

D-Ribo-phytosphingosine

C18 sphingonine

Unknown

Arachidonic (20:4)

Unknown

Homogamma linolenic (20:3)

C20 ceramide, 16:0-18:1 DG

Unknown

16:0-18:0 DG

Lignoceric acid (24:0)

Unknown

16:0 LPA

Unknown

Unknown

Unknown

Unknown

C20 ceramide,

16:0-18:1 DG

18:1-20:4 PA

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