The sphingomyelin metabolite, sphingosylphosphorylcholine (SPC) has been the subject of much recent interest and controversy. Studies have indicated that SPC naturally occurs in plasma and a constituent of lipoproteins. Synthesis is also increased in some pathological conditions. Research has demonstrated that SPC is a potentially important lipid mediator of cell type specific functions in major tissues, such as heart, blood vessels, skin, brain and immune system. These effects are regulated via a number of different intracellular signalling cascades, also dependent upon cell type. Initial reports identifying high affinity SPC receptors at first appeared to reinforce the physiological relevance of this sphingolipid. However, these studies have now been retracted. Some SPC effects have been shown be occur via plasma membrane receptors for the related sphingolipid, sphingosine 1-phosphate (S1P). Despite a lack of well-defined receptor signal transduction mechanisms and sparse pharmacological data, several key characteristics of SPC are now emerging. SPC can act as a mitogen in several different cell types and in certain circumstances, may also be a pro-inflammatory mediator. In this review, these actions of SPC are discussed with a view to understanding the potential physiological relevance of this sphingolipid.

Related sphingolipids, sphingosine 1‐phosphate (S1P) and sphingosylphosphorylcholine (SPC), have important effects on vascular smooth muscle. The aim of this study was to investigate the intracellular pathways regulated by S1P and SPC in rat cerebral artery. In cerebral arteries, S1P increased extracellular signal‐regulated kinase (ERK)1/2 phosphorylation (5.2±1.4‐fold increase) but did not activate p38 mitogen‐activated protein kinase (p38MAPK) as assessed by immunoblotting. In contrast, SPC increased p38MAPK phosphorylation (3.0±0.3‐fold increase) but did not stimulate ERK1/2. This differential activation was confirmed by measuring activation of heat shock protein (HSP) 27, a known downstream target of p38MAPK. Only SPC, but not S1P, activated HSP27. In enzymatically dispersed cerebral artery myocytes, SPC increased [Ca2+]i in a concentration‐dependent manner (peak response at 10 μM: 0.4±0.02 ratio units) as determined using the Ca2+ indicator, Fura 2. In contrast to S1P, the SPC‐induced [Ca2+]i increase did not involve intracellular release but was due to Ca2+ influx via L‐type Ca2+ channels. Despite differences in signalling, both S1P and SPC phosphorylated the transcription factor cAMP response element‐binding protein (CREB). S1P‐induced CREB activation was dependent on ERK1/2 and Ca2+‐calmodulin‐dependent protein kinase (CaMK) activation. CREB activation by SPC required both p38MAPK and CaMK activation, but not ERK1/2. In conclusion, S1P and SPC activate distinct MAP kinase isoforms and increase [Ca2+]i via different mechanisms in rat cerebral artery. This does not affect the ability of S1P or SPC to activate CREB, although this occurs via different pathways. British Journal of Pharmacology (2006) 147, 351–359. doi:

Inflammation has an important function in the development of cerebral vasospasm after subarachnoid hemorrhage (SAH); however, the mediators of this inflammatory response have not been clearly identified. In this study, we have investigated the potential function of two sphingolipids, which occur naturally in plasma and serum, sphingosylphosphorylcholine (SPC) and sphingosine 1-phosphate (S1P), to act as proinflammatory mediators in cerebral artery vascular smooth muscle (VSM) cells. In rat cerebral arteries, SPC but not S1P activated p38 mitogen-activated protein kinase (MAPK). Using transcription factor arrays, two proinflammatory transcription factors activated by SPC in cerebral arteries were identified-nuclear factor-jB and CCAAT-enhancerbinding protein. Both these transcription factors were activated by SPC in a p38MAPK-dependent manner. To determine whether this contributed to vascular inflammation, an inflammatory protein array was performed, which showed that SPC increased release of the chemokine monocyte chemoattractant protein-1 (MCP-1) in cultured rat VSM cells. This increase in MCP-1 expression was confirmed in cerebral arteries. The S1P did not increase MCP-1 release. Taken together, our results suggest that SPC, but not S1P, can act as a proinflammatory mediator in cerebral arteries. This may contribute to inflammation observed after SAH and may be part of the initiating event in vasospasm.

Increasing experimental evidence has demonstrated that sphingolipids are likely to have an important regulatory function in the cardiovascular system. Two sphingolipids released from activated platelets, and therefore of particular relevance, are S1P (sphingosine 1-phosphate) and SPC (sphingosylphosphocholine). Both S1P and SPC can act as vasoconstrictors and may modulate VSMC (vascular smooth muscle cell) phenotype, as observed during the pathogenesis of vascular disease. Recent research has suggested that SPC may act as a pro-inflammatory mediator in VSMCs and, in some circumstances, may also contribute to the development of vascular disease.