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


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.


CONCLUSIONS
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.
Wang
Wen-Yi
WY
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.
Li
Jie
J
Yang
Ding
D
Xu
Wei
W
Zha
Ruo-peng
RP
Wang
Yi-ping
YP
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism* / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000201:enzymology; D009000:Monocytes / Q000166:cytology / Q000201:enzymology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D008077:Lipoproteins, LDL; D012333:RNA, Messenger; C099252:oxidized low density lipoprotein; D019869:Phosphatidylinositol 3-Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase