Suppression of endothelial cell apoptosis by high density lipoproteins (HDL) and HDL-associated lysosphingolipids

J Biol Chem. 2001 Sep 14;276(37):34480-5. doi: 10.1074/jbc.M103782200. Epub 2001 Jun 29.


Apoptotic cell death following injury of vascular endothelium is assumed to play an important role in the pathogenesis of atherosclerosis. In this report, we demonstrate that high density lipoproteins (HDL), a major anti-atherogenic lipoprotein fraction, protect endothelial cells against growth factor deprivation-induced apoptosis. HDL blocked the mitochondrial pathway of apoptosis by inhibiting dissipation of mitochondrial potential (Deltapsi(m)), generation of reactive oxygen species, and release of cytochrome c into the cytoplasm. As a consequence, HDL prevented activation of caspases 9 and 3 and apoptotic alterations of the plasma membrane such as increase of permeability and translocation of phosphatidylserine. Treatment of endothelial cells with HDL induced activation of the protein kinase Akt, an ubiquitous transducer of anti-apoptotic signals, and led to phosphorylation of BAD, a major Akt substrate. Suppression of Akt activity both by wortmannin and LY-294002 or by a dominant negative Akt mutant abolished the anti-apoptotic effect of HDL. Two bioactive lysosphingolipids present in HDL particles, sphingosylphosphorylcholine and lysosulfatide, fully mimicked the survival effect of HDL by blocking the mitochondrial pathway of apoptosis and potently activating Akt. In conclusion, the present study identifies HDL as a carrier of endogenous endothelial survival factors and suggests that inhibition of endothelial apoptosis by HDL-associated lysosphingolipids may represent an important and novel aspect of the anti-atherogenic activity of HDL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Arteriosclerosis / prevention & control*
  • Cell Survival / drug effects
  • Cells, Cultured
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects*
  • Humans
  • Lipoproteins, HDL / pharmacology*
  • Mitochondria / drug effects
  • Phosphatidylinositol 3-Kinases / physiology
  • Phosphorylcholine / analogs & derivatives
  • Phosphorylcholine / pharmacology*
  • Protein Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / physiology
  • Proto-Oncogene Proteins c-akt
  • Psychosine / analogs & derivatives*
  • Psychosine / pharmacology*
  • Sphingosine / analogs & derivatives
  • Sphingosine / pharmacology*


  • Lipoproteins, HDL
  • Proto-Oncogene Proteins
  • sphingosine phosphorylcholine
  • Phosphorylcholine
  • Psychosine
  • psychosine-3'-sulfate ester
  • AKT1 protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Sphingosine