Lipoprotein-Associated Phospholipase A2 Regulates Macrophage Apoptosis via the Akt and Caspase-7 Pathways

Aim: Mutations in lipoprotein-associated phospholipase A2 (Lp-PLA2) are related to atherosclerosis. However, the molecular effects of Lp-PLA2 on atherosclerosis have not been fully investigated. Therefore, this study attempted to elucidate this issue. Methods: Monocytes were isolated from randomly s...

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Published in:Journal of Atherosclerosis and Thrombosis 2014/08/26, Vol.21(8), pp.839-853
Main Authors: Maeda, Toshinaga, Takeuchi, Keisuke, Xiaoling, Pang, Zankov, Dimitar P., Takashima, Naoyuki, Fujiyoshi, Akira, Kadowaki, Takashi, Miura, Katsuyuki, Ueshima, Hirotsugu, Ogita, Hisakazu
Format: Article
Language:English
Subjects:
1-Alkyl-2-acetylglycerophosphocholine Esterase - genetics
1-Alkyl-2-acetylglycerophosphocholine Esterase - metabolism
Adult
Aged
Animals
Apoptosis
Atherosclerosis
Blotting, Western
Caspase 7 - metabolism
Cell Proliferation
Cells, Cultured
Cercopithecus aethiops
COS Cells
Flow Cytometry
Heterozygote
Humans
Lipoproteins, LDL - metabolism
Macrophage
Macrophages - metabolism
Macrophages - pathology
Male
Middle Aged
Monocytes - metabolism
Monocytes - pathology
Mutation - genetics
Phospholipase
Proto-Oncogene Proteins c-akt - metabolism
Real-Time Polymerase Chain Reaction
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Summary:Aim: Mutations in lipoprotein-associated phospholipase A2 (Lp-PLA2) are related to atherosclerosis. However, the molecular effects of Lp-PLA2 on atherosclerosis have not been fully investigated. Therefore, this study attempted to elucidate this issue. Methods: Monocytes were isolated from randomly selected healthy male volunteers according to each Lp-PLA2 genotype (wild-type Lp-PLA2 [Lp-PLA2 (V/V)], the heterozygous V279F mutation [LpPLA2 (V/F)] and the homozygous V279F mutation [Lp-PLA2 (F/F)]) and differentiated into macrophages. The level of apoptosis in the macrophages following incubation without serum was measured using the annexin V/propidium iodide double staining method, and the underlying mechanisms were further examined using a culture cell line. Results: The average plasma Lp-PLA2 concentration [Lp-PLA2 (V/V): 129.4 ng/mL, Lp-PLA2 (V/F): 70.7 ng/mL, Lp-PLA2 (F/F): 0.4 ng/mL] and activity [Lp-PLA2 (V/V): 164.3 nmol/min/mL, LpPLA2 (V/F): 100.9 nmol/min/mL, Lp-PLA2 (F/F): 11.6 nmol/min/mL] were significantly different between each genotype, although the basic clinical characteristics were similar. The percentage of apoptotic cells was significantly higher among the Lp-PLA2 (F/F) macrophages compared with that observed in the Lp-PLA2 (V/V) macrophages. This induction of apoptosis was independent of the actions of acetylated low-density lipoproteins. In addition, the transfection of the expression plasmid of V279F mutant Lp-PLA2 into Cos-7 cells or monocyte/macrophage-like U937 cells promoted apoptosis. The knockdown of Lp-PLA2 also increased the number of apoptotic cells. Among the cells expressing mutant Lp-PLA2, the caspase-7 activity was increased, while the activated Akt level was decreased. Conclusions: The V279F mutation of Lp-PLA2 positively regulates the induction of apoptosis in macrophages and Cos-7 cells. An increase in the caspase-7 activity and a reduction in the activated Akt level are likely to be involved in this phenomenon.
ISSN:1340-3478
1880-3873
DOI:10.5551/jat.21386