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Hydroxyoctadecadienoic Acids Regulate Apoptosis in Human THP-1 Cells in a PPARγ-Dependent Manner

  • Original Article
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Lipids

Abstract

Macrophage apoptosis, a key process in atherogenesis, is regulated by oxidation products, including hydroxyoctadecadienoic acids (HODEs). These stable oxidation products of linoleic acid (LA) are abundant in atherosclerotic plaque and activate PPARγ and GPR132. We investigated the mechanisms through which HODEs regulate apoptosis. The effect of HODEs on THP-1 monocytes and adherent THP-1 cells were compared with other C18 fatty acids, LA and α-linolenic acid (ALA). The number of cells was reduced within 24 hours following treatment with 9-HODE (p < 0.01, 30 μM) and 13 HODE (p < 0.01, 30 μM), and the equivalent cell viability was also decreased (p < 0.001). Both 9-HODE and 13-HODE (but not LA or ALA) markedly increased caspase-3/7 activity (p < 0.001) in both monocytes and adherent THP-1 cells, with 9-HODE the more potent. In addition, 9-HODE and 13-HODE both increased Annexin-V labelling of cells (p < 0.001). There was no effect of LA, ALA, or the PPARγ agonist rosiglitazone (1μM), but the effect of HODEs was replicated with apoptosis-inducer camptothecin (10μM). Only 9-HODE increased DNA fragmentation. The pro-apoptotic effect of HODEs was blocked by the caspase inhibitor DEVD-CHO. The PPARγ antagonist T0070907 further increased apoptosis, suggestive of the PPARγ-regulated apoptotic effects induced by 9-HODE. The use of siRNA for GPR132 showed no evidence that the effect of HODEs was mediated through this receptor. 9-HODE and 13-HODE are potent—and specific—regulators of apoptosis in THP-1 cells. Their action is PPARγ-dependent and independent of GPR132. Further studies to identify the signalling pathways through which HODEs increase apoptosis in macrophages may reveal novel therapeutic targets for atherosclerosis.

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Abbreviations

HODEs :

Hydroxyoctadecadienoic acids

PPARγ :

Peroxisome proliferator-activated receptor gamma

GPR132 :

G protein-coupled receptor-132

15-LOX-1 :

15-Lipoxygenase-1

oxLDL :

Oxidised low-density lipoprotein

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Acknowledgments

James Cook University and the Private Practice Fund of the Townsville Hospital generously supported this work. We are grateful to Linda Thomas, Jason Hodge, and Stephen Garland for their technical assistance in the early stages of this work.

Conflict of interest

None of the authors has a conflict of interest to declare in relation to this work.

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Authors and Affiliations

  1. School of Medicine and Dentistry, James Cook University, Townsville, QLD, Australia

    Venkat N. Vangaveti, Venkatesh M. Shashidhar, Usman H. Malabu & Roy R. Rasalam

  2. School of Veterinary and Biomedical Sciences, James Cook University, Townsville, QLD, Australia

    Catherine Rush

  3. Department of Medicine, Faculty of Health, Deakin University, Waurn Ponds Campus, Geelong, VIC, 3220, Australia

    Fiona Collier & Richard L. Kennedy

  4. Department of Psychiatry, University of Adelaide, Adelaide, SA, Australia

    Bernhard T. Baune

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  1. Venkat N. Vangaveti
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Correspondence to Richard L. Kennedy.

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Vangaveti, V.N., Shashidhar, V.M., Rush, C. et al. Hydroxyoctadecadienoic Acids Regulate Apoptosis in Human THP-1 Cells in a PPARγ-Dependent Manner. Lipids 49, 1181–1192 (2014). https://doi.org/10.1007/s11745-014-3954-z

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