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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2510.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Phospholipase A₂–Modified Low-Density Lipoprotein Activates the Phosphatidylinositol 3-Kinase-Akt Pathway and Increases Cell Survival in Monocytic Cells

Dmitry Namgaladze; Bernhard Brüne

From Faculty of Medicine, Institute of Biochemistry I, Johann Wolfgang Goethe-University, Frankfurt, Germany.

Correspondence to Bernhard Brüne, Faculty of Medicine, Institute of Biochemistry I, Johann Wolfgang Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. E-mail bruene{at}zbc.kgu.de

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.

Methods and 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.

Monocyte survival is an important determinant in the development of atherosclerotic lesions. We show that phospholipase A₂-modified LDL activates phosphatidylinositol 3-kinase-Akt signaling and increases survival of monocytic cells. Our data provide a mechanistic explanation to understand pro-atherogenic actions of phospholipase A₂.

Key Words: apoptosis • atherosclerosis • low-density lipoprotein • monocytes • phospholipase A₂

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