High density lipoproteins (HDL) interrupt the sphingosine kinase signaling pathway. A possible mechanism for protection against atherosclerosis by HDL

J Biol Chem. 1999 Nov 12;274(46):33143-7. doi: 10.1074/jbc.274.46.33143.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arteriosclerosis / metabolism
  • Cell Adhesion Molecules / metabolism
  • Cells, Cultured
  • Ceramides / metabolism
  • E-Selectin / metabolism
  • Endothelium, Vascular / drug effects
  • Enzyme Activation / drug effects
  • Humans
  • Lipoproteins, HDL / pharmacology*
  • Lysophospholipids*
  • Mitogen-Activated Protein Kinases / metabolism
  • NF-kappa B / metabolism
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Signal Transduction*
  • Sphingomyelins / metabolism
  • Sphingosine / analogs & derivatives
  • Sphingosine / metabolism
  • Sphingosine / pharmacology
  • Tumor Necrosis Factor-alpha / pharmacology
  • Vascular Cell Adhesion Molecule-1 / metabolism

Substances

  • Cell Adhesion Molecules
  • Ceramides
  • E-Selectin
  • Lipoproteins, HDL
  • Lysophospholipids
  • NF-kappa B
  • Sphingomyelins
  • Tumor Necrosis Factor-alpha
  • Vascular Cell Adhesion Molecule-1
  • sphingosine 1-phosphate
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • Mitogen-Activated Protein Kinases
  • Sphingosine