High density lipoproteins (HDL) interrupt the sphingosine kinase signaling pathway. A possible mechanism for protection against atherosclerosis by HDL.
The ability of high density lipoproteins (HDL) to inhibit cytokine-induced adhesion molecule expression has been demonstrated in their protective function against the development of atherosclerosis and associated coronary heart disease. A key event in atherogenesis is endothelial activation induced by a variety of stimuli such as tumor necrosis factor-alpha (TNF), resulting in the expression of various adhesion proteins. We have recently reported that sphingosine 1-phosphate, generated by sphingosine kinase activation, is a key molecule in mediating TNF-induced adhesion protein expression. We now show that HDL profoundly inhibit TNF-stimulated sphingosine kinase activity in endothelial cells resulting in a decrease in sphingosine 1-phosphate production and adhesion protein expression. HDL also reduced TNF-mediated activation of extracellular signal-regulated kinases and NF-kappaB signaling cascades. Furthermore, HDL enhanced the cellular levels of ceramide which in turn inhibits endothelial activation. Thus, the regulation of sphingolipid signaling in endothelial cells by HDL provides a novel insight into the mechanism of protection against atherosclerosis.
Xia
P
P
Division of Human Immunology, Hanson Centre for Cancer Research, Institute of Medical Science, University of Adelaide, Adelaide, South Australia 5000, Australia.
Vadas
M A
MA
Rye
K A
KA
Barter
P J
PJ
Gamble
J R
JR
D001161:Arteriosclerosis / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism; D019040:E-Selectin / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008075:Lipoproteins, HDL / Q000494:pharmacology*; D008246:Lysophospholipids; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D015398:Signal Transduction; D013109:Sphingomyelins / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D000099157:Sphingosine Kinase
D015815:Cell Adhesion Molecules; D002518:Ceramides; D019040:E-Selectin; D008075:Lipoproteins, HDL; D008246:Lysophospholipids; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D017853:Phosphotransferases (Alcohol Group Acceptor); D013109:Sphingomyelins; D013110:Sphingosine; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate