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

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Author(s)

    • Maeda Toshinaga
    • Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology, Shiga University of Medical Science
    • Ogita Hisakazu
    • Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology, Shiga University of Medical Science
    • Takeuchi Keisuke
    • Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology, Shiga University of Medical Science
    • Xiaoling Pang
    • Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology, Shiga University of Medical Science
    • P. Zankov Dimitar
    • Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology, Shiga University of Medical Science
    • Miura Katsuyuki
    • Department of Health Science, Shiga University of Medical Science|Center for Epidemiologic Research in Asia, Shiga University of Medical Science
    • Ueshima Hirotsugu
    • Department of Health Science, Shiga University of Medical Science|Center for Epidemiologic Research in Asia, Shiga University of Medical Science

Abstract

<b><i>Aim</i></b>: 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.<br><b><i>Methods</i></b>: 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.<br><b><i>Results</i></b>: 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.<br><b><i>Conclusions</i></b>: 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.

Journal

  • Journal of Atherosclerosis and Thrombosis

    Journal of Atherosclerosis and Thrombosis 21(8), 839-853, 2014

    Japan Atherosclerosis Society

Codes

  • NII Article ID (NAID)
    130004845473
  • Text Lang
    ENG
  • ISSN
    1340-3478
  • Data Source
    J-STAGE 
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