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

作者：Vangaveti Venkat N; Shashidhar Venkatesh M; Rush Catherine; Malabu Usman H; Rasalam Roy R; Collier Fiona; Baune Bernhard T; Kennedy Richard L^*

来源：Lipids, 2014, 49(12): 1181-1192.

DOI：10.1007/s11745-014-3954-z

• Monocytes
• Macrophages
• Apoptosis
• Oxidized lipids

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 PPAR gamma 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 alpha-linolenic acid (ALA). The number of cells was reduced within 24 hours following treatment with 9-HODE (p %26lt; 0.01, 30 mu M) and 13 HODE (p %26lt; 0.01, 30 mu M), and the equivalent cell viability was also decreased (p %26lt; 0.001). Both 9-HODE and 13-HODE (but not LA or ALA) markedly increased caspase-3/7 activity (p %26lt; 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 %26lt; 0.001). There was no effect of LA, ALA, or the PPAR gamma agonist rosiglitazone (1 mu M), but the effect of HODEs was replicated with apoptosis-inducer camptothecin (10 mu M). Only 9-HODE increased DNA fragmentation. The pro-apoptotic effect of HODEs was blocked by the caspase inhibitor DEVD-CHO. The PPAR gamma antagonist T0070907 further increased apoptosis, suggestive of the PPAR gamma-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 PPAR gamma-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.

• 出版日期2014-12