title: Role for peroxisome proliferator-activated receptor alpha in oxidized phospholipid-induced synthesis of monocyte chemotactic protein-1 and interleukin-8 by endothelial cells.
abstract: The attraction, binding, and entry of monocytes into the vessel wall play an important role in atherogenesis. We have previously shown that minimally oxidized/modified LDL (MM-LDL), a pathogenically relevant lipoprotein, can activate human aortic endothelial cells (HAECs) to produce monocyte chemotactic activators. In the present study, we demonstrate that MM-LDL and oxidation products of 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphocholine (PAPC) activate endothelial cells to synthesize monocyte chemotactic protein-1 (MCP-1) and interleukin-8 (IL-8). Several lines of evidence suggest that this activation is mediated by the lipid-dependent transcription factor peroxisome proliferator-activated receptor alpha (PPARalpha), the most abundant member of the PPAR family in HAECs. Treatment of transfected CV-1 cells demonstrated activation of the PPARalpha ligand-binding domain by MM-LDL, Ox-PAPC, or its component phospholipids, 1-palmitoyl-2-oxovalaroyl-sn-glycero-phosphocholine and 1-palmitoyl-2-glutaroyl-sn-glycero-phosphocholine; these lipids also activated a consensus peroxisome proliferator-activated receptor response element (PPRE) in transfected HAECs. Furthermore, activation of PPARalpha with synthetic ligand Wy14,643 stimulates the synthesis of IL-8 and MCP-1 by HAECs. By contrast, troglitazone, a PPARgamma agonist, decreased the levels of IL-8 and MCP-1. Finally, we demonstrate that unlike wild-type endothelial cells, endothelial cells derived from PPARalpha null mice do not produce MCP-1/JE in response to Ox-PAPC and MM-LDL. Together, these data demonstrate a proinflammatory role for PPARalpha in mediation of the activation of endothelial cells to produce monocyte chemotactic activity in response to oxidized phospholipids and lipoproteins.
authors.affiliation: Division of Cardiology, Department of Medicine, University of California, Los Angeles, USA.
authors.forename: H
authors.initials: H
authors.lastname: Lee
authors.forename: W
authors.initials: W
authors.lastname: Shi
authors.forename: P
authors.initials: P
authors.lastname: Tontonoz
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.forename: G
authors.initials: G
authors.lastname: Subbanagounder
authors.forename: C C
authors.initials: CC
authors.lastname: Hedrick
authors.forename: S
authors.initials: S
authors.lastname: Hama
authors.forename: C
authors.initials: C
authors.lastname: Borromeo
authors.forename: R M
authors.initials: RM
authors.lastname: Evans
authors.forename: J A
authors.initials: JA
authors.lastname: Berliner
authors.forename: L
authors.initials: L
authors.lastname: Nagy
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D002460:Cell Line; D018932:Chemokine CCL2 / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis; D007546:Isoquinolines / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000378:metabolism; D010084:Oxidation-Reduction; D010742:Phospholipid Ethers / Q000494:pharmacology; D010743:Phospholipids / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D020218:Response Elements; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides; D014157:Transcription Factors / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D014162:Transfection
chemical_list: D018932:Chemokine CCL2; D016209:Interleukin-8; D007546:Isoquinolines; D008077:Lipoproteins, LDL; D010742:Phospholipid Ethers; D010743:Phospholipids; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; D014157:Transcription Factors; C099252:oxidized low density lipoprotein; C043051:1-O-hexadecyl-2-arachidonyl-sn-glycero-3-phosphocholine; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide