Wen-Yi Wang1, Jie Li, Ding Yang, Wei Xu, Ruo-peng Zha, Yi-ping Wang. 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.
Abstract
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.
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.
Authors: Alexander K Tsai; Brian T Steffen; Jose M Ordovas; Robert Straka; Xia Zhou; Naomi Q Hanson; Donna Arnett; Michael Y Tsai Journal: Transl Res Date: 2011-02-26 Impact factor: 7.012
Authors: Brian T Steffen; Lyn M Steffen; Shuang Liang; Russell Tracy; Nancy Swords Jenny; Michael Y Tsai Journal: Br J Nutr Date: 2013-04-03 Impact factor: 3.718