Phospholipase A2-modified low-density lipoprotein activates the phosphatidylinositol 3-kinase-Akt pathway and increases cell survival in monocytic cells.
OBJECTIVE
Monocyte survival is an important determinant in the development of atherosclerotic lesions. We investigated the influence of phospholipase A2-modified LDL (PLA-LDL), a pro-atherogenic factor, on activation of the pro-survival kinase Akt and cell death in monocytic cells.


RESULTS
PLA-LDL induced robust phosphorylation and activation of Akt in THP1 cells. It also attenuated oxidative stress-induced cell death, an effect abolished by phosphatidylinositol 3-kinase (PI3K) inhibition. In addition, PLA-LDL increased survival of human monocytes. We noticed that lipid products derived from LDL phospholipolysis are mediators of PLA-LDL-induced Akt activation. Arachidonic acid, which is released on phospholipase treatment of LDL, induced Akt phosphorylation and increased cell survival, whereas lysophosphatidylcholine, another compound generated by LDL phospholipolysis, induced only transient Akt phosphorylation and was cytotoxic.


CONCLUSIONS
Our data indicate that PLA-LDL induces activation of the PI3K-Akt pathway and promotes monocytic cell survival, which may contribute to the pro-atherogenic effects of phospholipase A2-modified LDL.
Namgaladze
Dmitry
D
Faculty of Medicine, Institute of Biochemistry I, Johann Wolfgang Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
Brüne
Bernhard
B
D016718:Arachidonic Acid / Q000494:pharmacology; D050197:Atherosclerosis / Q000209:etiology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003603:Cytotoxins / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D006801:Humans; D008066:Lipolysis; D008077:Lipoproteins, LDL / Q000008:administration & dosage / Q000187:drug effects* / Q000378:metabolism / Q000494:pharmacology*; D008244:Lysophosphatidylcholines / Q000494:pharmacology; D009000:Monocytes / Q000378:metabolism / Q000502:physiology*; D009994:Osmolar Concentration; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010741:Phospholipases A / Q000494:pharmacology*; D054467:Phospholipases A2; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D003603:Cytotoxins; D008077:Lipoproteins, LDL; D008244:Lysophosphatidylcholines; D016718:Arachidonic Acid; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D010741:Phospholipases A; D054467:Phospholipases A2