title: Hydroxyoctadecadienoic acids regulate apoptosis in human THP-1 cells in a PPARγ-dependent manner.
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 (1 μM), but the effect of HODEs was replicated with apoptosis-inducer camptothecin (10 μM). 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.
authors.affiliation: School of Medicine and Dentistry, James Cook University, Townsville, QLD, Australia.
authors.forename: Venkat N
authors.initials: VN
authors.lastname: Vangaveti
authors.forename: Venkatesh M
authors.initials: VM
authors.lastname: Shashidhar
authors.forename: Catherine
authors.initials: C
authors.lastname: Rush
authors.forename: Usman H
authors.initials: UH
authors.lastname: Malabu
authors.forename: Roy R
authors.initials: RR
authors.lastname: Rasalam
authors.forename: Fiona
authors.initials: F
authors.lastname: Collier
authors.forename: Bernhard T
authors.initials: BT
authors.lastname: Baune
authors.forename: Richard L
authors.initials: RL
authors.lastname: Kennedy
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D019787:Linoleic Acid / Q000494:pharmacology; D008041:Linoleic Acids / Q000494:pharmacology; D044243:Linoleic Acids, Conjugated / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology; D017962:alpha-Linolenic Acid / Q000494:pharmacology
chemical_list: D018797:Cell Cycle Proteins; C493410:FABP4 protein, human; D050556:Fatty Acid-Binding Proteins; D005231:Fatty Acids, Unsaturated; C115270:G2A receptor; D008041:Linoleic Acids; D044243:Linoleic Acids, Conjugated; D047495:PPAR gamma; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D045162:Thiazolidinediones; C495366:hydroxyoctadecadienoic acid; D000077154:Rosiglitazone; D017962:alpha-Linolenic Acid; C024347:9-hydroxy-10,12-octadecadienoic acid; C024348:13-hydroxy-9,11-octadecadienoic acid; D019787:Linoleic Acid; D053148:Caspase 3; D053179:Caspase 7