oxLDL Uptake Research Articles

Novel 5' exon of scavenger receptor CD36 is expressed in cultured human vascular smooth muscle cells and atherosclerotic plaques.

CD36, a member of the scavenger receptor family, is centrally involved in the uptake of oxidized low density lipoproteins (oxLDLs) from the bloodstream. During the atherosclerotic process, the lipid cargo of oxLDL accumulates in macrophages and smooth muscle cells (SMCs), inducing their pathological conversion to foam cells. Increased expression of CD36 occurs in human atherosclerotic lesions, and CD36 knockout mice show reduced uptake of modified LDLs and reduced atherosclerosis. Here, we describe a novel exon 1b and extended CD36 promoter in human SMCs. Exon 1b is specifically transcribed in activated aortic SMCs and mainly expressed in atherosclerotic plaques. Thus, switching to exon 1b transcription may be an important step for the activation of SMCs and their conversion to foam cells. Using an antisense oligonucleotide to exon 1b, we inhibit CD36 translation and highly reduce oxLDL uptake. The antisense to exon 1b does not affect CD36 in cell lines not expressing the new exon. The possibility of a novel antiatherosclerotic therapy and the use of exon 1b as a marker of atherosclerosis are discussed.

2231 繰り返しひずみの大きさがマクロファージの酸化 LDL 取り込みに及ぼす影響

2231 繰り返しひずみの大きさがマクロファージの酸化 LDL 取り込みに及ぼす影響

Statins inhibit oxidized-LDL-mediated LOX-1 expression, uptake of oxidized-LDL and reduction in PKB phosphorylation.

LOX-1, a lectin-like receptor on endothelial cells, facilitates the uptake of oxidized-LDL. Expression of LOX-1 is involved in the pathobiological effects of oxidized-LDL in endothelial cells, including apoptosis, suppression of cNOS activity and cell adhesion. Recent studies show that intracellular signal protein kinase B (PKB) is involved in the regulation of cNOS. Further, HMG CoA reductase inhibitors (statins) may affect LOX-1 expression. In this study, we examined the modulation of LOX-1 expression and PKB activity in response to oxidized-LDL by two different statins (simvastatin and atorvastatin). Cultured human coronary artery endothelial cells (HCAECs) were used in this study. Oxidized-LDL (40 microg/ml) was found to upregulate the expression of LOX-1 (mRNA and protein), enhance [125I]-ox-LDL uptake and to reduce the phosphorylation of PKB (p-PKB). Two different statins, simvastatin and atorvastatin (each 1 and 10 microM), upregulated the activity of PKB and decreased LOX-1 expression and [125I]-ox-LDL uptake. A high concentration of statins (10 microM) gave a more potent effect than the low concentration (1 microM). The effects of the two different statins were similar. These observations show that statins decrease LOX-1 expression, a novel oxidized-LDL endothelial receptor, and uptake of oxidized-LDL in HCAECs. The effect of statins on LOX-1 expression is associated with an increase in PKB activity in HCAECs.

Oxidized low-density lipoproteins bind to the scavenger receptor, CD36, of hepatic stellate cells and stimulate extracellular matrix synthesis

Cumulating evidence suggests that oxidative stress resulting in lipid peroxidation and protein modification is involved in the pathogenesis of chronic liver injury and fibrogenesis. We investigated the effects of oxidized low-density lipoproteins (oxLDL) on collagen and fibronectin synthesis of cultured human and rat hepatic stellate cells (HSC). As shown on protein and mRNA levels, oxLDL dose-dependently stimulated the synthesis of collagen types I and III and fibronectin of cultured HSC. The effect was biphasic, with a maximum between 5 and 25 microg/mL oxLDL (c-fibronectin concentration in HSC supernatants increased 3.9-fold; collagen type I increased 4-fold). Higher oxLDL concentrations were cytotoxic. LDL modified with malondialdehyde (MDA) was not toxic, but stimulated extracellular matrix synthesis as well. As demonstrated by immunofluorescence microscopy (double staining of CD36 and iso-alpha-smooth muscle actin [iso-alpha-sm actin]), immunoblot, and reverse-transcription polymerase chain reaction (RT-PCR), respectively, cultured human HSC express the oxLDL receptor, CD36 (glycoprotein IIIb). Colocalization of CD36 and iso-alpha-sm actin on sinusoidal lining cells was further demonstrated using sections of human fibrotic liver. Preincubation of cultured human HSC with the monoclonal antibody, OKM5, known to block CD36-mediated oxLDL uptake, resulted in a reduction of the oxLDL-stimulated collagen type I synthesis by 56%. In summary, our results demonstrate that low concentrations of modified lipoproteins (oxLDL and MDA-LDL) represent fibrogenic mediators that bind to CD36 and stimulate matrix synthesis of HSC.

The First Human Monoclonal Antibody to Oxidized LDL

Largely as a result of the seminal observations of Steinberg and colleagues1 on oxidized lipoproteins and the work of Witztum and his colleagues on the immunological response to these modified lipoproteins, there has been much recent interest in the significance and role of antibodies to oxidized LDL (oxLDL) in the plasma of humans and animals with evolving atherosclerosis. This interest has focused on the value of these antibodies for the diagnosis of atherosclerosis and, more important, in its pathogenesis. This story is now greatly advanced by the article from Witztum and colleagues (Shaw et al2) in this issue of the Journal, in which they report on the isolation and characterization of the first human monoclonal antibody that recognizes epitopes of oxLDL. These authors started with RNA extracted from peripheral blood mononuclear cells of a patient with coronary artery disease that were expressing high titers of antibody to malondialdehyde LDL (MDA-LDL). They used this RNA to prepare cDNA, from which they generated 2 phage (filamentous) display libraries expressing the variable chains of heavy and light immunoglobulins with both the k and l light-chain families. These libraries were screened against MDA-LDL through several rounds. Three specific IgG antibodies were isolated that bind MDA-LDL. One of these antibodies, 1K 17, was characterized in some detail with respect to its immunological and biological properties. This antibody bound to the lipid and protein moieties of oxLDL but not to native LDL. 1K 17 also recognized apoptotic cells. It inhibited the uptake of both oxLDL and apoptotic cells by macrophages in culture. It was used to immunostain human and …

Pomegranate Juice Supplementation to Atherosclerotic Mice Reduces Macrophage Lipid Peroxidation, Cellular Cholesterol Accumulation and Development of Atherosclerosis

Inhibition of lipid peroxidation contributes to the attenuation of macrophage cholesterol accumulation, foam-cell formation and atherosclerosis. Evidence suggests that nutritional antioxidants such as pomegranate juice (PJ) can contribute to the reduction of oxidative stress and atherogenesis. The goals of the present study were to determine whether such beneficial effects of PJ exist when supplemented to apolipoprotein E-deficient (E(0)) mice with advanced atherosclerosis and to analyze the antiatherosclerotic activity of a tannin-fraction isolated from PJ. Mice (4-mo-old) were supplemented with PJ in their drinking water for 2 mo and compared with age-matched placebo-treated mice, as well as to young (4-mo-old) control mice, for their mouse peritoneal macrophage (MPM) oxidative state, cholesterol flux and mice atherosclerotic lesion size. PJ supplementation reduced each of the proatherogenic variables determined in the present study compared with age-matched placebo-treated mice. It significantly induced serum paraoxonase activity and reduced MPM lipid peroxide content compared with placebo-treated mice and control mice. PJ administration to E(0) mice significantly reduced the oxidized (Ox)-LDL MPM uptake by 31% and MPM cholesterol esterification and increased macrophage cholesterol efflux by 39% compared with age-matched, placebo-treated mice. PJ consumption reduced macrophage Ox-LDL uptake and cholesterol esterification to levels lower than those in 4-mo-old, unsupplemented controls. PJ supplementation to E(0) mice with advanced atherosclerosis reduced the lesion size by 17% compared with placebo-treated mice. In a separate study, supplementation of young (2-mo-old) E(0) mice for 2 mo with a tannin fraction isolated from PJ reduced their atherosclerotic lesion size, paralleled by reduced plasma lipid peroxidation and decreased Ox-LDL MPM uptake. PJ supplementation to mice with advanced atherosclerosis reduced their macrophage oxidative stress, their macrophage cholesterol flux and even attenuated the development of atherosclerosis. Moreover, a tannin-fraction isolated from PJ had a significant antiatherosclerotic activity.

Induction of the OxLDL Receptor LOX-1 by Endothelin-1 in Human Endothelial Cells

In this study, we analyzed the effect of endothelin-1 (ET-1) on expression of the lectin-like oxidized low-density lipoprotein (oxLDL) receptor-1 LOX-1 and on oxLDL uptake in primary cultures of human umbilical vein endothelial cells (HUVEC). LOX-1 mRNA was quantified by standard-calibrated competitive RT-PCR, LOX-1 protein expression by Western analysis and endothelial oxLDL uptake using DiI-labeled oxLDL. ET-1 induces LOX-1 mRNA expression, reaching its maximum after 1 h (160 ± 14% of control, 100 nM ET-1, P < 0.05). This increased ET-1-mediated LOX-1 mRNA expression could be inhibited by endothelin receptor B antagonist BQ-788. In addition, ET-1 stimulates LOX-1 protein expression and oxLDL uptake in HUVEC. The augmented oxLDL uptake by ET-1 is mediated by endothelin receptor B, but not by protein kinases. These data support a new pathophysiological mechanism how locally and systemically increased ET-1 levels could promote LOX-1-mediated oxLDL uptake in human endothelial cells and the development and progression of endothelial dysfunction and atherosclerosis.

Substrate-Bound Fibronectin Enhances Scavenger Receptor Activity of Macrophages by Calcium Signaling

We have previously found that ability of mouse macrophages to bind and take up oxidized low-density lipoprotein (oxLDL) through scavenger receptors is significantly enhanced when the cells are plated on fibronectin (FN)-coated culture substrates. Here, the mechanisms of the enhancement of the scavenger receptor activity by the substrate-bound FN was investigated using thioglycollate-induced mouse peritoneal macrophages. A Ca2+ channel blocker diltiazem and a calmodulin inhibitor W-7 reduced the scavenger receptor activity of the macrophages plated on FN-coated substrate to the level of the cells plated on uncoated substrate, as assessed by oxLDL binding, while the scavenger receptor activity of the macrophages on uncoated substrate was little affected. Similarly, FN-induced enhancement of the scavenger receptor activity assessed by oxLDL uptake was selectively inhibited by Ca2+ channel blockers (diltiazem, nifedipine, verapamil) and calmodulin inhibitors (W-7, trifluoperazine). Intracellular free Ca2+ level of the macrophages was increased, depending on extracellular Ca2+, when plated on FN-coated substrate. This increase in the Ca2+ level was inhibited by diltiazem and RGD-containing peptides present in cell adhesive region of FN. Like the substrate-bound FN, Ca2+ ionophore A23187 enhanced the scavenger receptor activity of binding and taking up of oxLDL. These results indicate that substrate-bound FN enhances scavenger receptor activity of macrophages by increasing channel-dependent Ca2+ influx. A microtubule disruptor, colchicine, and an actin filament disruptor, cytochalasin B, inhibited the FN-induced enhancement of the scavenger receptor activity, suggesting that these cytoskeletal structures are required for transmission of the adhesion signal of FN. The number of the scavenger receptors was found to increase by 1.4-fold upon adhesion signal of FN. We suggest that substrate-bound FN increases the number of the macrophage scavenger receptors as a result of induction of Ca2+ influx and causes increased accumulation of oxLDL within the cells, rendering the cells more susceptible to conversion into foam cells.

Induction of CD36 by all-trans retinoic acid: retinoic acid receptor signaling in the pathogenesis of atherosclerosis.

Scavenger receptors mediating the uptake of oxidized low-density lipoproteins (oxLDL) by macrophages play a crucial role in foam cell formation during atherosclerosis. One member of this receptor family, the thrombospondin receptor CD36, has recently been shown to mediate a major part of the oxLDL-induced aggravation of atherosclerotic lesions. Here, we show that the expression of CD36 protein and mRNA in human monocytic THP-1 cells is increased by all-trans retinoic acid (atRA), a derivative of the essential Vitamin A, which leads to increased uptake of oxLDL. CD3106, a specific antagonist at the retinoic acid receptor (RAR), inhibited the atRA-induced CD36 expression, whereas the RAR-specific agonist CD367 induced CD36 to the same degree as atRA. This indicates an RAR-mediated CD36 induction. AtRA and oxLDL had synergistic effects in up-regulating CD36 when in both THP-1 cells and primary monocytes. Applying a sensitive RAR-GAL-4 reporter assay, we could demonstrate RAR ligands in human atherosclerotic lesions. In addition, immunohistochemistry showed RAR-a and -g in the lesions, which indicates that atRA may contribute to foam cell formation and the progress of atherosclerosis.

Prevention of atherosclerosis by specific AT1-receptor blockade with candesartan cilexetil.

Several studies indicate that blockade of the renin-angiotensin-aldosterone system (RAAS) can prevent atherosclerosis and vascular events, but the precise mechanisms involved are still unclear. In this study, we investigated the effect of the AT 1-receptor blocker, candesartan, in the prevention of atherosclerosis in Watanabe heritable hyperlipidaemic (WHHL) rabbits and also the effect of AT1-receptor blockade in the uptake of oxidised LDL by macrophage cell cultures. In the first set of experiments, 12 WHHL rabbits were randomly assigned to three groups: placebo, atenolol 5 mg/kg daily or candesartan 2 mg/kg daily for six months. Compared with controls and atenolol-treated rabbits, candesartan treatment resulted in a significant 50-60% reduction of atherosclerotic plaque formation and a 66% reduction in cholesterol accumulation in the thoracic aorta. Studies in macrophage cultures indicated that candesartan prevented uptake of oxidised LDL-(oxLDL)-cholesterol by cultured macrophages. Candesartan inhibited the uptake of oxLDL in a dose-dependent manner, reaching a maximum inhibition of 70% at concentrations of 5.6 µg/ml. Further studies in other animal models and well-designed trials in humans are warranted to further explore the role of AT1-receptor blockade in the prevention of atherosclerosis.

Oxidized LDL upregulates angiotensin II type 1 receptor expression in cultured human coronary artery endothelial cells: the potential role of transcription factor NF-kappaB.

We demonstrated earlier that angiotensin II (Ang II), by AT(1) receptor activation, upregulates oxidized LDL (ox-LDL) endothelial receptor LOX-1 gene expression and uptake of ox-LDL in human coronary artery endothelial cells (HCAECs). In this study, we investigated the regulation of Ang II receptors (AT1R and AT2R) by ox-LDL and the role of the redox-sensitive transcription factor NF-kappaB in this process. HCAECs were incubated with ox-LDL for 24 hours. Ox-LDL (10 to 40 microg protein/mL) upregulated AT1R but not AT2R, mRNA, or protein. Ox-LDL degraded IkappaBalpha in cytoplasm and activated transcription factor NF-kappaB (P65) in HCAEC nuclear extract. Treatment of cells with the antioxidant alpha-tocopherol (10 to 50 micromol/L) attenuated ox-LDL-mediated degradation of IkappaBalpha and activation of NF-kappaB (P65) and inhibited the upregulation of AT1R mRNA and protein. The role of NF-kappaB signal transduction was further examined by use of an NF-kappaB inhibitor, caffeic acid phenethyl ester (CAPE). Pretreatment of cells with CAPE inhibited ox-LDL-mediated degradation of IkappaBalpha and NF-kappaB activation and inhibited ox-LDL-induced upregulation of AT1R expression. Incubation of cells with both ox-LDL and Ang II increased cell injury, measured as cell viability and LDH release, compared with either ox-LDL or Ang II alone. alpha-Tocopherol as well as the specific AT1R blocker CV11974 (candesartan) attenuated the cell-injurious effects of ox-LDL. These observations suggest an important role of ox-LDL-mediated AT1R upregulation in cell injury. In this process, NF-kappaB activation seems to play a critical role in signal transduction. These findings provide a basis for the use of antioxidants and AT1R blockers in designing therapy of atherosclerosis.

CD36 scavenger receptor expression and oxLDL uptake are inhibited by vitamin E

Conference Abstract| October 01 2000 CD36 scavenger receptor expression and oxLDL uptake are inhibited by vitamin E R. Ricciarelli; R. Ricciarelli 1Büblstrasse, 28 3012 Bern Switzerland Search for other works by this author on: This Site PubMed Google Scholar T. M. Zingg; T. M. Zingg 1Büblstrasse, 28 3012 Bern Switzerland Search for other works by this author on: This Site PubMed Google Scholar A. Azzi A. Azzi 1Büblstrasse, 28 3012 Bern Switzerland Search for other works by this author on: This Site PubMed Google Scholar Biochem Soc Trans (2000) 28 (5): A242. https://doi.org/10.1042/bst028a242a Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Twitter LinkedIn Cite Icon Cite Get Permissions Citation R. Ricciarelli, T. M. Zingg, A. Azzi; CD36 scavenger receptor expression and oxLDL uptake are inhibited by vitamin E. Biochem Soc Trans 1 October 2000; 28 (5): A242. doi: https://doi.org/10.1042/bst028a242a Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu nav search search input Search input auto suggest search filter All ContentAll JournalsBiochemical Society Transactions Search Advanced Search This content is only available as a PDF. © 2000 Biochemical Society2000 Article PDF first page preview Close Modal You do not currently have access to this content.

ENHANCEMENT OF OXIDISED LOW-DENSITY LIPOPROTEIN UPTAKE BY MACROPHAGES IN RESPONSE TO MACROPHAGE MIGRATION INHIBITORY FACTOR

We examined the expression of macrophage migration inhibitory factor (MIF) mRNA in murine macrophage cell line (RAW 264.7 cells) in response to oxidized low-density lipoprotein (oxLDL), and investigated the influence of MIF on the uptake and degradation of oxLDL by RAW 264.7 cells. MIF mRNA expression was markedly upregulated in the presence of oxLDL. Consistent with this, the MIF level of the culture medium was increased by stimulation with oxLDL in dose- and time-dependent manners. Next, we added recombinant rat MIF to the culture medium and examined its effects on the uptake of125I-labelled oxLDL. Pretreatment with MIF enhanced both the uptake and degradation of125I-oxLDL. Taken together, these results suggest that MIF released from macrophages in response to oxLDL stimulates oxLDL uptake and degradation in an autocrine and paracrine fashion, which potentially results in atherosclerosis.

Vitamin E reduces the uptake of oxidized LDL by inhibiting CD36 scavenger receptor expression in cultured aortic smooth muscle cells.

Vitamin E is well known as an antioxidant, and numerous studies suggest that it has a preventive role in atherosclerosis, although the mechanism of action still remains unclear. The original aim of this study was to establish whether alpha-tocopherol (the most active form of vitamin E) acts at the earliest events on the cascade of atherosclerosis progression, that of oxidized LDL (oxLDL) uptake and foam-cell formation. We show here that the CD36 scavenger receptor (a specific receptor for oxLDL) is expressed in cultured human aortic smooth muscle cells (SMCs). Treatment of SMCs and HL-60 macrophages with alpha-tocopherol (50 micromol/L, a physiological concentration) downregulates CD36 expression by reducing its promoter activity. Furthermore, we find that alpha-tocopherol treatment of SMCs leads to a reduction of oxLDL uptake. This study indicates that CD36 is expressed in cultured human SMCs. In these cells, CD36 transports oxLDL into the cytosol. alpha-Tocopherol inhibits oxLDL uptake by a mechanism involving downregulation of CD36 mRNA and protein expression. Therefore, the beneficial effect of alpha-tocopherol against atherosclerosis can be explained, at least in part, by its effect of lowering the uptake of oxidized lipoproteins, with consequent reduction of foam cell formation.

Angiotensin II increases macrophage uptake of Ox-LDL and CD36 mRNA expression: Possible role of IL-6 and inhibitory effects of fosinopril and losartan

Angiotensin II increases macrophage uptake of Ox-LDL and CD36 mRNA expression: Possible role of IL-6 and inhibitory effects of fosinopril and losartan

1411 繰り返しひずみがマクロファージの泡沫化に及ぼす影響

1411 繰り返しひずみがマクロファージの泡沫化に及ぼす影響

Shosaikoto as a potential antiatherosclerotic agent.

Shosaikoto, a Kampo medicine used clinically to treat patients with chronic hepatitis or cirrhosis in Japan, displays immunoregulatory effects, especially on macrophage functions. Oral administration of shosaikoto influences the synthesis of humoral factors such as the interleukins, nitric oxide and prostaglandins in macrophages. In addition, phagocytic activity is enhanced by treatment with shosaikoto, resulting in an antigen that is effectively presented to T lymphocytes to produce more antibodies. The role of macrophages in the pathogenesis of atherosclerosis is well recognized, although a therapeutic agent targeted at macrophages has not yet been developed. When shosaikoto was administered to atherosclerotic rabbits, it did not exhibit antihyperlipidemic effects but did reduce the formation of atherosclerotic lesions. In addition, treatment with shosaikoto suppressed intimal hyperplasia in apoE-deficient mice fed a cholesterol-enriched diet for nine weeks. Biochemical studies demonstrated that the mechanism of the antiatherosclerotic effect was partly due to the increase of oxidized low-density lipoprotein (oxLDL) elimination by macrophages, resulting from stimulation of oxLDL uptake through scavenger receptors, activation of acyl-CoA:cholesterol acyltransferase and neutral cholesteryl ester hydrolase, and increase of cholesterol elimination by high-density lipoprotein. Furthermore, shosaikoto is able to reverse the depression of macrophage functions caused by hyperlipidemia. These results indicate the potential of this medicine as a new type of preventive or therapeutic agent for atherosclerosis.

Upregulation of endothelial receptor for oxidized low-density lipoprotein (LOX-1) in cultured human coronary artery endothelial cells by angiotensin II type 1 receptor activation.

Cross talk between oxidized LDL (ox-LDL) and angiotensin II (Ang II) may be relevant in atherosclerosis. In this study, we examined the presence of a specific endothelial receptor for ox-LDL (LOX-1) and Ang II receptors in human coronary artery endothelial cells (HCAECs). In addition, we studied the effect of Ang II on LOX-1 gene and protein expression. LOX-1 was consistently identified in HCAECs by reverse transcriptase-polymerase chain reaction (RT-PCR), cDNA sequence, Western blot, and 125I-labeled ox-LDL binding assay (Bmax, 29.7 ng/mg protein). The HCAECs also exhibited Ang II receptors (AT1>AT2), as determined by RT-PCR and 125I-labeled Ang II binding assay (Bmax, 2.21 and 1.19 fmol/mg protein, respectively). Incubation of HCAECs with Ang II markedly increased LOX-1 mRNA (RT-PCR) and protein (Western blot) expression. The increase in LOX-1 expression was dependent on Ang II concentration (10(-12) to 10(-6) mol/L). Ang II caused a concentration-dependent increase in 125I-labeled ox-LDL uptake by HCAECs and enhanced ox-LDL-mediated cell injury, as evident from an increase in LDH release and a decrease in cell viability. These effects of Ang II were completely blocked by pretreatment of HCAECs with losartan, a specific AT1 blocker, but not by PD123319, a specific AT2 blocker. These observations indicate the following: (1) HCAECs possess abundant LOX-1 as well as Ang II (AT1>AT2) receptors, (2) Ang II upregulates LOX-1 receptor and ox-LDL uptake, (3) the effects of Ang II are mediated by AT1 activation, and (4) Ang II enhances ox-LDL-mediated injury to HCAECs.

Identification and Autoregulation of Receptor for OX-LDL in Cultured Human Coronary Artery Endothelial Cells

Although macrophages scavenge oxidatively modified low density lipoprotein (ox-LDL) via specific receptors, the uptake of ox-LDL by endothelial cells is thought to be mediated by a different receptor (LOX-1). We examined the presence of LOX-1 on cultured human coronary artery endothelial cells (HCAECs) by RT-PCR, radioligand blot, and binding assays. LOX-1 mRNA and protein were consistently identified in HCAECs. [125I]-ox-LDL binding assay also identified high affinity binding sites for LOX-1 on HCAECs (KD:1.71 × 10−8M: Bmax:29.7 ng/mg protein). There was no change in LOX-1 expression in HCAECs treated with native-LDL. In contrast, incubation of HCAECs with ox-LDL (10–40 μg/ml) increased LOX-1 expression (mRNA and protein). The upregulation of LOX-1 expression appeared to be dependent on ox-LDL concentration. Higher concentration (100 μg/ml) however, decreased LOX-1 expression, perhaps related to its cytotoxic effect. These observations indicate that ox-LDL upregulates its own receptor on HCAECs. This phenomenon may explain enhanced uptake of ox-LDL by HCAECs in hyperlipidemia resulting in cellular dysfunction.

PPARγ Promotes Monocyte/Macrophage Differentiation and Uptake of Oxidized LDL

The formation of foam cells from macrophages in the arterial wall is characterized by dramatic changes in lipid metabolism, including increased expression of scavenger receptors and the uptake of oxidized low-density lipoprotein (oxLDL). We demonstrate here that the nuclear receptor PPARγ is induced in human monocytes following exposure to oxLDL and is expressed at high levels in the foam cells of atherosclerotic lesions. Ligand activation of the PPARγ:RXRα heterodimer in myelomonocytic cell lines induces changes characteristic of monocytic differentiation and promotes uptake of oxLDL through transcriptional induction of the scavenger receptor CD36. These results reveal a novel signaling pathway controlling differentiation and lipid metabolism in monocytic cells, and suggest that endogenous PPARγ ligands may be important regulators of gene expression during atherogenesis.