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.