Sphingosylphosphorylcholine is a Proinflammatory Mediator in Cerebral Arteries

Abstract

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.

Ceramide 1-phosphate induces macrophage chemoattractant protein-1 release: involvement in ceramide 1-phosphate-stimulated cell migration

“…Of note, two related phosphosphingolipid mediators, sphingosine phosphorylcholine (SPC) and S1P, also induced secretion of proinflammatory MCP-1 in human umbilical vein endothelial cells (34) and vascular smooth muscle cells (54), and human mast cells (42), respectively. As for C1P, the stimulating effect of SPC on MCP-1 secretion was also dependent on activation of a specific, albeit still not well-defined, receptor (40).…”

Critical Role of the Sphingolipid Pathway in Stroke: a Review of Current Utility and Potential Therapeutic Targets

“…(14, 15) It is elevated in some pathological conditions(32–37) and was recently discovered as a pro-inflammatory mediator in cerebral arteries. (38) This, combined with previous evidence on a correlation with post-SAH vasospasm,(32, 37) makes SPC a promising novel target in stroke worthy of further investigation.…”

“…Further, SPC cerebrospinal fluid (CSF) levels are elevated in SAH patients. (32, 37, 38, 176) Moreover, sphingolipids and CSF ceramide alterations after SAH have also been detected and correlate with clinical outcome. In the CSF of patients with SAH, ceramide is increased and an activation of sphingomyelinae (ASMase), S1P-lyase, and glucosylceramide synthase (GCS) lead to an alteration in the production of protective (S1P) in favor of deleterious (Ceramide) sphingolipids.…”

“…(32, 37, 38, 175–179) S1P was first found to induce vasoconstriction in canine basilar artery and SPC was determined to be a novel mediator of Rho-kinase induced cerebral vasospasm and act as a proinflammatory mediator in cerebral arteries. Further, SPC cerebrospinal fluid (CSF) levels are elevated in SAH patients.…”

Novel effects of sphingosylphosphorylcholine on invasion of breast cancer: Involvement of matrix metalloproteinase-3 secretion leading to WNT activation

“…Increased levels of SPC are found in atopic dermatitis, Niemann-Pick disease (NPD), and malignant ascites of patients with tumors [15][16][17]. SPC induces the scratching response in mice via degranulation of mast cells and is also a proinflammatory mediator in cerebral arteries [18][19][20]. SPC levels are reportedly increased in plasma of metabolic syndrome patients [21].…”