Article

Sphingosylphosphorylcholine induces apoptosis of endothelial cells through reactive oxygen species-mediated activation of ERK.

Medical Research Center for Ischemic Tissue Regeneration and Medical Research Institute, College of Medicine, Pusan National University, Busan 602-739, Republic of Korea.
Journal of Cellular Biochemistry (impact factor: 2.87). 05/2007; 100(6):1536-47. DOI:10.1002/jcb.21141 pp.1536-47
Source: PubMed

ABSTRACT Sphingosylphosphorylcholine (SPC) produces reactive oxygen species (ROS) in MS1 pancreatic islet endothelial cells. In the present study, we explored the physiological significance of the SPC-induced ROS generation in endothelial cells. SPC induced cell death of MS1 cells at higher than 10 microM concentration through a caspase-3-dependent pathway. SPC treatment induced sustained activation of an extracellular signal-regulated kinase (ERK), in contrast to transient activation of ERK in response to platelet-derived growth factor (PDGF)-BB, which stimulated proliferation of MS1 cells. Both the SPC-induced cell death and ERK activation were abolished by pretreatment of the cells with the MEK inhibitor U0126 or by overexpression of a dominant negative mutant of MEK1 (DN-MEK1). Pretreatment of the cells with N-acetylcysteine, an antioxidant, completely prevented the SPC-induced ROS generation, apoptosis, and ERK activation, whereas the ROS generation was not abrogated by treatment with U0126. Consistent with these results, SPC induced cell death of human umbilical vein endothelial cells (HUVECs) through ROS-mediated activation of ERK. These results suggest that the SPC-induced generation of ROS plays a crucial role in the cell death of endothelial cells through ERK-dependent pathway.

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    Article: Sphingosylphosphorylcholine reduces the organ injury/dysfunction and inflammation caused by endotoxemia in the rat.
    Oliver Murch, Maha Abdelrahman, Massimo Collino, Margherita Gallicchio, Elisa Benetti, Emanuela Mazzon, Roberto Fantozzi, Salvatore Cuzzocrea, Christoph Thiemermann
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    ABSTRACT: Sphingosylphosphorylcholine (SPC) has been reported to activate a variety of G-protein coupled receptors, including S1P(1-5), G2A, GPR4, and OGR1 (GPR68). Interestingly, other structurally related lysophospholipid agonists of these receptors have been shown to exhibit immunomodulatory properties both in vitro and in vivo. These include prevention of tumor necrosis factor-alpha-induced monocyte adhesion to aortic endothelium in mice (sphingosine-1-phosphate via S1P(1-5) receptors) and reduction of organ injury and/or mortality in animal models of sepsis and endotoxemia (lysophosphatidylcholine via G2A). Here, we investigate the effects of SPC on the organ injury/dysfunction caused by systemic administration of lipopolysaccharide and the mechanisms underlying the observed effects of SPC. Prospective, randomized study. University-based research laboratory. Sixty-one anesthetized male Wistar rats. Rats received either SPC (10 mg/kg intravenously) or vehicle (phosphate-buffered saline 1 mL/kg intravenously) 15 mins before or 15 mins after induction of endotoxemia with lipopolysaccharide (6 mg/kg intravenously). Treatment with SPC significantly reduced the organ/dysfunction injury caused by lipopolysaccharide. SPC pretreatment significantly reduced the circulating levels of interleukin-1beta and interleukin-6, the expression of CD11b (ligand for intercellular adhesion molecule-1) on circulating polymorphonuclear cells, the expression of proteins of intercellular adhesion molecule-1 (Western blot and immunohistochemistry), cyclooxygenase-2 and nuclear translocation of nuclear factor-kappaB (Western blot analysis), and inducible nitric oxide synthase (immunohistochemistry) as well as the lung injury caused by endotoxemia in the rat. SPC reduced the organ injury/dysfunction caused by endotoxin in the rat. These beneficial effects of SPC are associated with potent anti-inflammatory effects.
    Critical care medicine 03/2008; 36(2):550-9. · 6.37 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

10 microM concentration
 
caspase-3-dependent pathway
 
cell death
 
crucial role
 
dominant negative mutant
 
endothelial cells
 
ERK-dependent pathway
 
extracellular signal-regulated kinase
 
human umbilical vein endothelial cells
 
MEK inhibitor U0126
 
MS1 cells
 
MS1 pancreatic islet endothelial cells
 
platelet-derived growth factor
 
reactive oxygen species
 
ROS generation
 
SPC induced cell death
 
SPC treatment induced
 
SPC-induced cell death
 
SPC-induced generation
 
SPC-induced ROS generation
 

Eun Su Jeon