ORIGINAL ARTICLE Hydroxyoctadecadienoic Acids Regulate Apoptosis in Human THP-1 Cells in a PPARc-Dependent Manner Venkat N. Vangaveti • Venkatesh M. Shashidhar • Catherine Rush • Usman H. Malabu • Roy R. Rasalam • Fiona Collier • Bernhard T. Baune • Richard L. Kennedy Received: 31 March 2014 / Accepted: 11 September 2014 / Published online: 21 October 2014 Ó AOCS 2014 Abstract Macrophage apoptosis, a key process in ath- erogenesis, is regulated by oxidation products, including hydroxyoctadecadienoic acids (HODEs). These stable oxidation products of linoleic acid (LA) are abundant in atherosclerotic plaque and activate PPARc 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 a-linolenic acid (ALA). The number of cells was reduced within 24 hours following treatment with 9-HODE (p \ 0.01, 30 lM) and 13 HODE (p \ 0.01, 30 lM), 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 label- ling of cells (p \ 0.001). There was no effect of LA, ALA, or the PPARc agonist rosiglitazone (1lM), but the effect of HODEs was replicated with apoptosis-inducer camptothe- cin (10lM). Only 9-HODE increased DNA fragmentation. The pro-apoptotic effect of HODEs was blocked by the caspase inhibitor DEVD-CHO. The PPARc antagonist T0070907 further increased apoptosis, suggestive of the PPARc-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—regu- lators of apoptosis in THP-1 cells. Their action is PPARc- dependent and independent of GPR132. Further studies to identify the signalling pathways through which HODEs increase apoptosis in macrophages may reveal novel ther- apeutic targets for atherosclerosis. Keywords Monocytes Á Macrophages Á Apoptosis Á Oxidized lipids Abbreviations HODEs Hydroxyoctadecadienoic acids PPARc Peroxisome proliferator-activated receptor gamma GPR132 G protein-coupled receptor-132 15-LOX-1 15-Lipoxygenase-1 oxLDL Oxidised low-density lipoprotein Introduction Linoleic acid (LA; C18:2), an omega-6 fatty acid, is the most abundant polyunsaturated fatty acid in atherosclerotic plaque, and its stable oxidation products, hydroxyoctade- cadienoic acids (HODEs), accumulate in the low-density V. N. Vangaveti Á V. M. Shashidhar Á U. H. Malabu Á R. R. Rasalam School of Medicine and Dentistry, James Cook University, Townsville, QLD, Australia C. Rush School of Veterinary and Biomedical Sciences, James Cook University, Townsville, QLD, Australia F. Collier Á R. L. Kennedy (&) Department of Medicine, Faculty of Health, Deakin University, Waurn Ponds Campus, Geelong, VIC 3220, Australia e-mail: richardlee.k@hotmail.com B. T. Baune Department of Psychiatry, University of Adelaide, Adelaide, SA, Australia 123 Lipids (2014) 49:1181–1192 DOI 10.1007/s11745-014-3954-z