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Cardiovascular Research Advance Access first published online on November 12, 2009
This version [Corrected Proof] published online on December 1, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp367
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

OxLDL stimulates lipoprotein-associated phospholipase A2 expression in THP-1 monocytes via PI3K and p38 MAPK pathways

Wen-Yi Wang1,2, Jie Li1, Ding Yang1, Wei Xu1,2, Ruo-peng Zha1,2 and Yi-ping Wang1,*

1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China
2 Graduate School of the Chinese Academy of Sciences, Beijing, China

* Corresponding author. Tel: +86 21 5080 6733, Fax: +86 21 5080 7088, Email: ypwang{at}mail.shcnc.ac.cn

Aims: Lipoprotein-associated phospholipase A2 (lp-PLA2) has been detected in human and rabbit atherosclerotic lesions, where it co-localizes with its substrate, oxidized LDL (oxLDL). Here, we investigated whether oxLDL may exert a regulatory effect on lp-PLA2 expression.

Methods and results: Using human monocytic THP-1 cells as a model system, we found that oxLDL up-regulated the expression of lp-PLA2 while another substrate of the enzyme, platelet activating factor, had no such effect. The up-regulatory effect of oxLDL could be conferred by its oxidized phospholipids (oxPCs, the exact substrates of lp-PLA2), but not their hydrolyzed products, lysophosphatidylcholines (lysoPCs). OxLDL induced the activation of p38 mitogen-activating protein kinase (MAPK) through phosphatidylinositol 3-kinase (PI3K). Inhibition of either PI3K or p38 MAPK completely blocked oxLDL-induced lp-PLA2 expression. In addition, inhibition of lp-PLA2 activity in the conditioned medium significantly decreased lipid accumulation in macrophages as detected by oil red staining.

Conclusion: The present study shows that oxLDL, and more specifically its unhydrolyzed oxidized phospholipids, can up-regulate lp-PLA2 expression in monocytes through the PI3K and p38 MAPK pathway. In turn, lp-PLA2 promotes lipoprotein uptake in macrophages. Our results uncover a new link between oxLDL and lp-PLA2, and may provide insight into this interaction in the context of atherosclerosis.

KEYWORDS Atherosclerosis; lp-PLA2; oxLDL; p38; PI3K

Time for primary review: 24 days


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