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(Circulation Research. 2000;87:516.)
© 2000 American Heart Association, Inc.

Molecular Medicine

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

Hans Lee, Weibin Shi, Peter Tontonoz, Shirley Wang, Ganesamoorthy Subbanagounder, Catherine C. Hedrick, Susan Hama, Christine Borromeo, Ronald M. Evans, Judith A. Berliner, Laszlo Nagy

From the Division of Cardiology (H.L., W.S., S.W., G.S., L.H., S.H., C.B., J.A.B.), Department of Medicine, and Department of Pathology (J.A.B.), University of California, Los Angeles; The Salk Institute of Biological Studies (P.T., R.M.E., L.N.); and Howard Hughes Medical Institute (R.M.E.), La Jolla, Calif. Present address for L.N. is University of Debrecen, Medical and Health Science Center, Department of Biochemistry and Molecular Biology, Debrecen, Hungary; present address for P.T. is Department of Pathology, University of California, Los Angeles.

Correspondence to Judith A. Berliner, PhD, Department of Pathology and Medicine, UCLA School of Medicine, 13-239 Center for the Health Sciences, 650 Charles Young Dr, Los Angeles, CA 90095-1732. E-mail jberliner{at}mednet.ucla.edu

	Abstract

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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 (PPAR), the most abundant member of the PPAR family in HAECs. Treatment of transfected CV-1 cells demonstrated activation of the PPAR 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 PPAR with synthetic ligand Wy14,643 stimulates the synthesis of IL-8 and MCP-1 by HAECs. By contrast, troglitazone, a PPAR agonist, decreased the levels of IL-8 and MCP-1. Finally, we demonstrate that unlike wild-type endothelial cells, endothelial cells derived from PPAR null mice do not produce MCP-1/JE in response to Ox-PAPC and MM-LDL. Together, these data demonstrate a proinflammatory role for PPAR in mediation of the activation of endothelial cells to produce monocyte chemotactic activity in response to oxidized phospholipids and lipoproteins.

Key Words: atherosclerosis • lipoproteins • phospholipids • interleukins • monocyte chemotactic protein-1 • endothelium

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References

 
The migration of monocytes into the vessel wall is fundamental to the pathogenesis of atherosclerosis. There is considerable evidence that oxidized lipids play an important role in this recruitment.^{1 2} Our laboratory demonstrated that the treatment of human aortic endothelial cells (HAECs) with minimally oxidized/modified LDL (MM-LDL) can stimulate monocyte endothelial interactions by increasing synthesis of specific monocyte adhesion molecules and monocyte activators.^{1 3} The levels of these induced molecules are all elevated in fatty streak lesions. Oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphocholine (Ox-PAPC) and 3 of its component phospholipids, 1-palmitoyl-2-oxovalaroyl-sn-glycero-phosphocholine (POVPC), 1-palmitoyl-2-glutaroyl-sn-glycero-phosphocholine (PGPC), and 1-palmitoyl-2-(5,6-epoxyisoprostane E₂)-sn-glycero-3-phosphocholine (PEIPC), were found to play a major role in the activation of endothelial cells by MM-LDL.^{4 5} These compounds are increased in atherosclerotic lesions, and antibodies that recognize them are detected in apoE-null mice, suggesting their in vivo relevance.⁴ Our group has demonstrated that the treatment of endothelial cells with MM-LDL, Ox-PAPC, and POVPC leads to an increase in cAMP levels and that this increase (inhibitable by H-89) was critical to the induction of monocyte binding.^{6 7}

In the present study, we examined the mechanism by which MM-LDL and bioactive phospholipids stimulate endothelial production of monocyte activators (chemotactic factors), monocyte chemotactic protein-1 (MCP-1), and interleukin-8 (IL-8). We hypothesized that peroxisome proliferator-activated receptors (PPARs), a group of lipid-activated transcription factors, may play a role in this stimulation. PPARs are transcription factors that bind to regulatory regions of target genes and activate transcription in response to the binding of lipid-like molecules.^{8 9 10 11} Three PPAR family members are known: , , and . The function of the ubiquitously expressed PPAR is not yet clear. Both PPAR and PPAR have been linked to signaling by lipids and inflammatory mediators. We present evidence to suggest that PPAR may play an important role in mediation of the induction of monocyte chemotactic factors by oxidized phospholipids.

	Materials and Methods

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Preparation of Cells and Lipids
CV-1 cells were obtained from American Type Culture Collection. Human aortic endothelial cells (HAECs) were isolated and maintained as described previously and used at passages 4 to 8.¹² PPAR-null mice on a C57Bl6/J background were generated as described.¹³ Endothelial cells from the thoracic aorta of mice (MAECs) were isolated and cultured (passages 2 to 4) as described previously; purity was 95%.¹⁴ Human monocytes were isolated according to the modified Recalde method.¹⁵ LDL and MM-LDL were prepared and fractionated as described previously.⁴ Ox-PAPC, PGPC, and PEIPC were prepared according to previously described methods.^{4 5 6} POVPC was prepared through the ozonolysis of PAPC.¹⁶ All oxidized lipids contained <0.001 pg/mL lipopolysaccharide (LPS).

Measurement of Levels of PPAR mRNA With TaqMan Real-Time RT-PCR
Total cell RNA was collected from HAECs and human monocytes and treated with DNase, and PPAR and PPAR were amplified with TaqMan real-time RT-PCR as described previously.¹⁷ Human PPAR was amplified with sense primer 5'-CCTTTTT-GTGGCTGCTATC-3' and antisense primer 5'-GTGGAG-TCTGAGCACATGT-3'. PPAR was amplified with sense primer 5'-TGAAGAGCCTTCCAACTCCCT-3' and antisense primer 5'-GAACTCCATAGTGAAATCCAGAAGC-3'. PPAR reaction produced a 106-bp PCR product, and PPAR reaction produced an 80-bp PCR product. The amplification reaction also contained the following TaqMan probes (100 nmol/L each): PPAR probe 5'-ATCGTCCTGGCCTTCTAAACGTAG-(FAM)-3' and PPAR probe 5'-TCTCCACAGACACGACATTCAATTGCCA-(FAM)-3'. All reactions were coamplified with human GAPDH probes and primers obtained from Perkin–Elmer Biosystems.

Measurement of Peroxisome Proliferator-Activated Receptor Response Element (PPRE) and PPAR Activation
To determine whether oxidized phospholipids activate PPAR in HAECs, cells were transfected with PPRE₃-TK-LUC construct¹⁸ (0.5 µg/well) and pCMX-ß-galactosidase (0.5 µg/well) with Superfect Transfection Reagent (Qiagen). Approximately 15% transfection efficiency was determined with plasmid that expresses green fluorescent protein. The cells were treated with either M199 supplemented with 10% resin-charcoal–stripped FBS alone or the indicated compounds for 16 hours. The luciferase units were normalized with the corresponding ß-galactosidase activity. To compare the activation of PPAR, PPAR, and PPAR by oxidized lipoproteins and lipids, we used a ligand activation assay with a chimeric receptor that contains the ligand-binding domain of PPAR, PPAR, or PPAR fused to the DNA binding domain of the yeast transcriptional activator GAL4 as described previously.^{18 19}

Chemokine Assays
To measure chemokine levels in the conditioned medium, cells were preincubated for 16 hours with M199 supplemented with 0.8 mg/mL human lipoprotein-deficient serum (HAECs) or DME that contained 1% FBS (MAECs); they were then treated for 4 hours with lipids, Wy14,643 (Chemsyn or BIOMOL), or troglitazone (Sankyo). In some experiments, HAECs were pretreated for 30 minutes with 2.5 µmol/L H-89 before the addition of the oxidized phospholipids. Wy14,643 and troglitazone contained <0.001 pg/mL LPS. Medium was used to assay levels of IL-8 or MCP-1 (HAECs) or MCP-1/JE (MAECs) with Quantikine kits (R and D Systems). RNA was harvested from HAECs for measurement of MCP-1 and IL-8 mRNA levels with RiboQuant Multi-Probe RNase protection kit (PharMingen).

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
Quantification of PPARs in HAECs
The levels of PPAR and PPAR mRNA in HAECs and human monocytes were determined with TaqMan real-time RT-PCR. PPAR was found to be the most abundantly expressed PPAR in HAECs. The ratio of to was 5.06. By contrast, the ratio of to in monocytes was 0.043. We conclude that although both receptors are present HAECs, it is likely that PPAR is the dominant receptor.

Oxidized Phospholipids and PPAR Agonist Increase and PPAR Agonist Decreases the Production of IL-8 and MCP-1 by HAECs: Effects of Oxidized Phospholipids Are Not Inhibited by H-89
Previous studies from our laboratory have demonstrated that the treatment of endothelial cells with MM-LDL increased the level of monocyte chemotactic activity in the medium and increased synthesis of MCP-1.²⁰ We now show that the oxidized phospholipids from MM-LDL, Ox-PAPC, POVPC, and PGPC increase both IL-8 (Figure 1A) and MCP-1 (Figure 1B) protein synthesis (levels of IL-8 and MCP-1 in medium from Ox-PAPC–treated cells averaged 7 and 1 ng/mL, respectively). Unlike the induction of monocyte binding, the cAMP pathway was not involved in the induction of IL-8 or MCP-1 synthesis, because protein levels were not different in cells pretreated for 30 minutes with 2.5 µmol/L H-89 (increase in IL-8: Ox-PAPC 620±40%, Ox-PAPC+H-89 601±35%; increase in MCP-1: Ox-PAPC 213±10%, Ox-PAPC+H-89 181±13%). To test the hypothesis that PPAR was involved in the increased synthesis of IL-8 and MCP-1 effects of Wy14,643 and troglitazone were also examined. HAEC were treated for 4 hours with, 20 µmol/L Wy14,643 (a level shown to be a PPAR specific²¹ ) or 20 µmol/L troglitazone (a level shown to be PPAR specific). Wy14,643 significantly increased the level of IL-8 (Figure 1A) and MCP-1 (Figure 1B). Wy14,643 increased chemokine production at concentrations from 5 to 10 µmol/L in separate experiments. In contrast, troglitazone decreased IL-8 (Figure 1A) and MCP-1 (Figure 2B) synthesis. Troglitazone also strongly inhibited the ability of Ox-PAPC to increase IL-8 synthesis, whereas Wy14,643 had no significant effect (Figure 1C). Troglitazone displayed a similar inhibitory effect on MCP-1 synthesis (data not shown). In a separate experiment, in which MCP-1 and IL-8 protein levels were increased 100% and 200%, respectively, mRNA (after 4 hours of treatment) for MCP-1 and IL-8 was also significantly increased by Ox-PAPC (MCP-1 40%, IL-8 80%) as determined with RNase protection assay. Pretreatment of HAEC with actinomycin D completely abolished the increases in MCP-1 and IL-8 (data not shown). We conclude that oxidized phospholipids and Wy14,643 increase the levels of IL-8 and MCP-1 mRNA and protein, whereas a PPAR agonist decreases the levels. Ox-PAPC, the most active lipid, was not toxic to the cells at 50 µg/mL as measured by the amount of ¹⁴C released from endothelial cells containing ¹⁴C-labeled ATP. This method has been shown to provide an early measure of toxicity.^{22 23}

View larger version (18K): [in this window] [in a new window]   Figure 1. Effect of oxidized phospholipids and PPAR agonists on IL-8 (A) and MCP-1 (B) protein synthesis. A and B, HAECs were treated with Ox-PAPC, POVPC, and PGPC (50, 10, and 5 µg/mL, respectively), 20 µmol/L Wy14,643, or 20 µmol/L troglitazone (Trog). The medium was used for IL-8 and MCP-1 ELISA. Both sets of data are expressed as percent above/below the untreated cells. *P<0.001, **P<0.05. C, HAECs were either treated with Ox-PAPC alone (12.5, 25, or 50 µg/mL) or cotreated with either 20 µmol/L troglitazone or 20 µmol/L Wy14,643 for 4 hours. The medium was collected and subjected to IL-8 ELISA. *P<0.001. The data are expressed in ng/mL. All data are representative of 3 different experiments.

View larger version (14K): [in this window] [in a new window]   Figure 2. Effect of oxidized phospholipids and a PPAR agonist on the activation of transiently transfected PPRE in HAEC cultures. HAECs at 50% to 80% confluence were cotransfected with PPREx3-TK-LUC and pCMX-ß-galactosidase. The cells were treated for 16 hours with 50 µg/mL Ox-PAPC, 5 µg/mL POVPC, 2.5 µg/mL PGPC, or 20 µmol/L Wy14,643. Luciferase/galactosidase ratios were determined. Data from a representative of 3 experiments are shown. Values are mean±SD (n=3). *P<0.001.

Oxidized Phospholipids Activate PPARs
To determine whether oxidized phospholipids can activate PPAR-dependent signaling in endothelial cells, HAECs were transfected with a reporter plasmid containing a consensus PPRE upstream of a luciferase gene. Wy14,643, as well as Ox-PAPC, PGPC, and POVPC, activated endogenous PPARs to induce the transcription of the PPRE-luciferase reporter gene (Figure 2). To determine which PPAR was activated, CV-1 monkey kidney fibroblasts were transiently transfected with the GAL4-PPAR, -PPAR, or -PPAR expression vectors and UAS-luciferase reporter and assayed for response to modified lipoproteins and oxidized phospholipids. MM-LDL in contrast to native LDL activated the PPAR ligand-binding domain, and most of this activity could be attributed to the oxidized phospholipid (PL) present in the lipoprotein; activity was not found in fatty acids or neutral lipids (Figure 3). Ox-PAPC, the most active MM-LDL component, but not native PAPC, dose dependently activated the PPAR transcriptional response (Figure 4A). To identify the specific bioactive lipid responsible for activation, we tested the effects of 2 components of Ox-PAPC, namely POVPC and PGPC in the reporter assay. As shown in Figure 4B, both POVPC and PGPC activated PPAR at concentrations of 1 to 5 µg/mL (1 to 7 µmol/L). Neither MM-LDL, Ox-PAPC, phospholipid components of MM-LDL, or POVPC significantly activated PPAR. However, PGPC activated PPAR 2-fold at the highest concentration used compared with the 8-fold increase in PPAR activation. None of the compounds activated PPAR.

View larger version (25K): [in this window] [in a new window]   Figure 3. Activation of PPAR by modified lipoproteins and oxidized phospholipids. CV-1 cells were transiently transfected with the chimeric receptor GAL4-DBD-PPAR-ligand-binding domain and an appropriate reporter gene (MH100-TK-Luciferase) containing GAL4 binding sites. Transfected cells were treated with increasing concentrations of native LDL, MM-LDL and MM-LDL fractions, neutral lipids (NL), fatty acids (FA), and polar lipids (PL) taken from the same amount of MM-LDL. Normalized luciferase activity was determined. Values are mean±SD (n>3). A representative experiment from 3 experiments is shown.

View larger version (23K): [in this window] [in a new window]   Figure 4. Activation of PPAR by defined phospholipids. A, Ox-PAPC and PAPC. B, POVPC and PGPC. The transcriptional activation of PPAR by oxidized phospholipids was compared in transient transfection experiments as described in Figure 3. Normalized luciferase activity was determined. Values are mean±SD (n>3). A representative experiment from 3 experiments is shown. *P<0.001.

Decreased Response to Ox-PAPC and MM-LDL by Aortic Endothelial Cells From PPAR-Null Mice
To test directly the role of PPAR in the induction of MCP-1/JE by oxidized phospholipids, aortic endothelial cell cultures from PPAR-null mice and wild-type mice on the C57Bl6/J background were exposed to LPS, Ox-PAPC, or MM-LDL for 4 hours. The levels of MCP-1/JE were measured with ELISA (Figure 5). Although there was considerable variation between the wild-type and PPAR-null mice, the mean increases in response to LPS were 1006% and 1136% above control, respectively, and were not significantly different in the 2 strains. In response to MM-LDL, wild-type cells showed dramatic increases in JE, ranging from 700% to 2500%, whereas PPAR-null endothelial cells did not respond to the MM-LDL and actually showed a small decrease. Native LDL did not induce MCP-1/JE production by either strain of mice (data not shown). In response to Ox-PAPC, PPAR-null MAEC displayed a mean decrease in MCP-1/JE (-37%), compared with a mean increase of 77% in cultures from wild-type endothelial cells. These experiments suggest that PPAR-dependent signaling has an important role in maintenance of the basal expression level of MCP-1/JE and mediation of the increase in MCP-1/JE in response to Ox-PAPC and MM-LDL.

View larger version (21K): [in this window] [in a new window]   Figure 5. Comparison of Ox-PAPC- and MM-LDL–induced MCP-1/JE in aortic endothelial cells derived from C57BL6/J wild-type or PPAR-null mice. Cells were treated for 4 hours with LPS (2 ng/mL), Ox-PAPC (50 µg/mL), or MM-LDL (250 µg/mL). The medium was collected, and levels of MCP-1/JE were determined by ELISA. The percent increase/decrease, compared with the levels in untreated cells, is shown. The actual MCP-1/JE protein in MM-LDL–treated cells averaged 300 pg/mL. We used, 13 mice from each strain for LPS treatment, 9 mice from each strain for Ox-PAPC treatment, and 4 wild-type and 6 PPAR-null mice for MM-LDL treatment. *P<0.001.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
These results provide evidence that PPAR plays an important role in the effects of MM-LDL, and its component oxidized phospholipids on endothelial synthesis of monocyte activators. The increased production of MCP-1 and IL-8 was not inhibited by H-89 pretreatment, suggesting that the cAMP pathway was not involved. Several lines of evidence from the current study support a role for the PPAR pathway. PPAR has previously been reported to be present in endothelial cells.^{24 25} Quantification of mRNA levels revealed that unlike monocytes, PPAR is expressed at higher levels than PPAR in HAECs. Our studies demonstrate that ligand activation of PPAR by Wy14,643 in HAECs leads to increased production of monocyte chemotactic factors MCP-1 and IL-8 protein (Figures 1A and 1B) and mRNA. We have shown that oxidized phospholipids activate a PPRE reporter transfected into HAECs and activate PPAR in CV-1 cells (Figures 2, 3, and 4). The most direct evidence for a role for PPAR in the action of Ox-PAPC was the finding that induction of MCP-1/JE synthesis in response to MM-LDL or Ox-PAPC was essentially abolished in PPAR-null aortic endothelial cells (Figure 5). Thus, our studies definitively demonstrate a role for PPAR in the induction of MCP-1/JE by Ox-PAPC and MM-LDL in mouse aortic endothelial cells. They suggest (because of PPRE activation and Wy14,643-induced increases) that PPAR also plays a role in MCP-1 and IL-8 induction by oxidized phospholipids in HAECs. Interestingly, the PPAR activator troglitazone inhibited basal IL-8 synthesis as well as that stimulated by Ox-PAPC (Figure 1C). This is similar to the findings of Su et al,²⁶ which showed that troglitazone and other known PPAR ligands inhibit the induction of MCP-1 and IL-8 in colonic epithelial cells. In vivo studies have shown that PPAR and PPAR agonists exert differing effects on metabolism.²⁷ Furthermore, knockouts of PPAR and PPAR have very different phenotypes.^{13 28}

Based on previous studies, there are several possible mechanisms by which these bioactive phospholipids could stimulate PPAR activation. The oxidized phospholipids (Ox-PL) could serve as ligands for PPARs. However, it is unlikely that oxidized phospholipids would move to the nucleus and bind to the PPAR receptor. A second possibility is that hydrolytic products of the bioactive phospholipids might activate PPARs. However, hydrolytic products of Ox-PAPC did not increase MCP-1 or IL-8 or activate PPAR- or PPAR-dependent transcriptional activity (data not shown). Based on past studies, we suggest that Ox-PL activates a second messenger pathway, such as the lipoxygenase (LO) pathway, producing PPAR ligands. Our group and others have shown that LO products can activate PPARs and are ligands for both and .^{10 29 30 31 32} Our group has shown that the treatment of HAECs with MM-LDL increases the production of LO products and that inhibition of this pathway blocks the induction of monocyte binding.³³ This second messenger system would represent a novel lipid activation pathway. In this pathway, an oxidized phospholipid would induce the generation of endogenous lipid ligand for PPARs through binding to a surface receptor and subsequent activation of 12/15-LO. Studies with 12/15-LO–null animals suggest an important role for this molecule in atherogenesis.³⁴ It is also possible that the oxidized phospholipids generate an as-yet-unidentified, high-affinity ligand through the activation of a different pathway. The existence of a ligand-independent activation pathway for PPAR also cannot be excluded at this point.

Although the present study demonstrates a proinflammatory effect of PPAR activation, previous studies from our group and others have reported anti-inflammatory roles of PPARs in cytokine- or LPS-induced activation. These studies have demonstrated inhibition of endothelin-1, human vascular cell adhesion molecule-1 and vascular smooth muscle cell activation, as well as the induction of interleukin-6 in response to PPAR activation.³⁵ Some of our group has shown inhibition of LPS-induced vascular cell adhesion molecule expression by Wy14,643 in HAECs.²⁵ Here we report specific proinflammatory effects of PPAR activation in the absence of cytokines or LPS. The actions of PPAR agonists in HAEC are thus similar to our previously reported effects of MM-LDL and oxidized phospholipids on specific inflammatory responses. These agents are proinflammatory when added to cells in the absence of cytokines and LPS but inhibit several proinflammatory effects of LPS and tumor necrosis factor.⁶ The behavior of PPAR in endothelial cells is similar to that of PPAR in macrophages, which also depends on cell context. PPAR ligands have been documented to suppress cytokine gene expression in activated macrophages^{36 37} but to induce gene expression in nonactivated monocytes.^{10 30} We thus hypothesize that the transcription factors assembled on the promoter are different in the presence and the absence of cytokines and LPS.

It is important to consider the implications of our studies for the use of PPAR agonists such as drugs (fibrates) in the treatment of atherosclerosis. Systemic treatment results in the simultaneous activation of many PPAR pathways. The overall effect of PPAR agonists on atherosclerosis has been shown to be beneficial, probably because of their effects on lipid levels. However, this does not preclude a role for PPAR in mediation of the induction of inflammatory genes in the vessel wall in response to endogenous ligands present in atherosclerotic lesions. This latter effect of PPAR agonist may, in particular context, have clinical significance; and interference in this pathway could, in some settings, be therapeutic.

In summary, the present study demonstrates that PPAR plays a role in mediation of the effects of oxidized phospholipids on endothelial cell synthesis of monocyte activators MCP-1 and IL-8. In separate studies, we have observed that the levels of Ox-PAPC products in aortas of animals with atherosclerotic lesions are 2- to 10-fold more than required to increase MCP-1 and IL-8,³⁸ which supports their in vivo relevance to atherosclerosis. Thus, our group, in the present and past studies, has identified several mechanisms by which PPAR activators may be proinflammatory and potentially proatherogenic, as summarized in Figure 6. Others have identified settings in which the activation of PPARs may be anti-inflammatory. Taken together, results from the present and past studies from our group and others suggest that the role of PPAR activation may differ in different inflammatory settings or may involve multiple signaling pathways.

View larger version (28K): [in this window] [in a new window]   Figure 6. Potential role for PPAR and PPAR in endothelial cell and monocyte activation. PPAR is the dominant isoform in endothelial cells. It can be activated by oxidized phospholipids. Activation leads to chemokine production and monocyte attraction and chemotaxis. PPAR is the predominant isoform in monocytes. It can be activated by component lipids present in Ox-LDL, which leads to monocyte maturation, CD36 expression, and Ox-LDL uptake.

	Acknowledgments

 
This work was supported by grant HL-30568 and the Laubisch Fund (to Dr Berliner). We acknowledge the excellent technical help of Henry Jugulion and Jackie Alvarez. Dr Evans is an Investigator of the Howard Hughes Medical Institute at the Salk Institute for Biological Studies and a March of Dimes Chair in Molecular and Developmental Biology. Dr Nagy is on leave from the Department of Biochemistry and Molecular Biology, University Medical School of Debrecen, Hungary, and was supported by a Special Fellowship from the Leukemia Society of America and by the Boehringer Ingelheim Research Award.

Received April 25, 2000; revision received July 5, 2000; accepted July 25, 2000.

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