Role for Peroxisome Proliferator-Activated Receptor α in Oxidized Phospholipid–Induced Synthesis of Monocyte Chemotactic Protein-1 and Interleukin-8 by Endothelial Cells

Division of Cardiology, Department of Medicine, University of California, Los Angeles, USA.
Circulation Research (Impact Factor: 11.02). 10/2000; 87(6):516-21. DOI: 10.1161/01.RES.87.6.516
Source: PubMed


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.

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Available from: Laszlo Nagy
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    • "OxPC could act as a peroxisome proliferator activating receptor (PPAR)-γ activator to induce inflammatory and metabolic responses [14]. It promotes chemokine production in endothelial cells [15,16] and proliferation and calcification of smooth muscle cells [17]. In addition, oxPC induces inflammatory reactions by acting as an environmental pathogen mimetic [18]. "
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    ABSTRACT: Oxidized phosphatidylcholines (oxPC) and lysophosphatidylcholine (lysoPC) generated during the formation of oxidized low-density lipoprotein (oxLDL) are involved in atherosclerotic lesion development. We investigated the time course-changes in phosphatidylcholine (PC) molecular species during oxidation of LDL to determine how those atherogenic PCs are produced. Human and rabbit LDLs were pretreated with or without a selective platelet-activating factor acetylhydrolase (PAF-AH) inhibitor. LDL was oxidized by incubation with copper sulfate, and PC profiles were analyzed by liquid chromatography-tandem mass spectrometry. When human LDL was oxidized, the peak areas for polyunsaturated fatty acid (PUFA)-containing PC species dramatically decreased after a short lag period, concomitantly lysoPC species increased sharply. Although a variety of oxPC species containing oxidized fatty acyl groups or cleaved acyl chains are formed during LDL oxidation, only a few oxPC products accumulated in oxLDL: 1-palmitoyl-2-(9-oxo-nonanoyl) PC and long-chain oxPC with two double bonds. Pretreatment of LDL with the PAF-AH inhibitor greatly reduced lysoPC production while it had no effect on lipid peroxidation reactions and oxPC profiles. Rabbit LDL, which has a different composition of PC molecular species and needs a longer time to reach achieve full oxidation than human LDL, also accumulated lysoPC during oxidation. The increase in lysoPC in rabbit oxLDL was suppressed by pretreatment with the PAF-AH inhibitor. The major oxPC species formed in rabbit oxLDL were almost the same as human oxLDL. These results suggest that lysoPC species are the major products and PAF-AH activity is crucial for lysoPC generation during oxidation of LDL. The oxPC species accumulated are limited when LDL is oxidized with copper ion in vitro.
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    • "PPARα is expressed in human aortic endothelial cells, carotid artery endothelial cells, and human umbilical vein endothelial cells.[11121314] "
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    ABSTRACT: There are controversial reports about the antiangiogenic effects of peroxisome proliferator-activated receptor α (PPARα). In the current study, we compared the effects of PPARα agonist and antagonist on human umbilical vein endothelial cells (HUVECs) angiogenesis with matrigel assay. HUVECs (1 × 10(5) cells/well) treated with PPARα agonist (fenofibrate) and antagonist (GW6471) were cultured on matrigel for 24 h. Treated cells were stained with calcein and investigated by fluorescent microscopy. The obtained images were also analyzed by AngioQuant software. Finally, the data were analyzed using SPSS 15 software, Kruskal-Wallis and one way ANOVA. Statistical analysis showed that fenofibrate significantly inhibit the tube formation (size, length, junction) (P < 0.05) but there was a trend to increased angiogenesis in GW6471 treated group (P > 0.05). These results showed that PPARα agonist is effective in suppression of angiogenesis. Further studies are needed to confirm these results in in vivo studies.
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    • "In previous works, the PAPC oxidation products have been studied for its effect on inflammation and showed ability to stimulate several cell types and various signal-transducing pathways as reviewed elsewhere (Bochkov et al., 2010). IL-8 is the best documented cytokine known to be increased due to OxPL stimulation (Bochkov et al., 2010; Lee et al., 2000; Subbanagounder et al., 2002a,b). Also, it has been reported that in human derived macrophages TNF-␣, IL-6 and IL-1␤ production can be enhanced by oxidized PC (Pegorier et al., 2006; Vladykovskaya et al., 2011). "
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