Involvement of multiple scavenger receptors in advanced glycation end product-induced vessel tube formation in endothelial cells.

Toxic advanced glycation end products (toxic AGEs) derived from glycolaldehyde (AGE3) have been implicated in the development of diabetic vascular complications such as retinopathy characterised by excessive angiogenesis. Different receptor types, such as receptor for AGEs (RAGE), Toll like receptor-4 and scavenger receptors, are expressed in endothelial cells and contribute to AGE-elicited alteration of cell function. In the present study, we examined the involvement of AGE-related receptors on AGE-induced angiogenesis in endothelial cells. The effects of pharmacological inhibitors or receptor neutralizing antibodies on AGE3-induced tube formation were investigated using the in vitro Matrigel tube formation assay in b.End5 cells (mouse endothelial cells). AGE3-induced signalling pathways and receptor expression changes were analysed by Western blot analysis and flow cytometry, respectively. Both FPS-ZM1, a RAGE inhibitor, and fucoidan, a ligand for scavenger receptors, suppressed AGE3-induced tube formation. Cocktails of neutralizing antibodies against the scavenger receptors CD36, CD163 and LOX-1 prevented AGE3-induced tube formation. AGE3 activated mTOR signalling, resulting in facilitation of tube formation. Activation of the AGE-RAGE pathway also led to the upregulation of scavenger receptors. Taken together, our findings suggest that the scavenger receptors CD36, CD163 and LOX-1 in conjunction with the RAGE receptor work together to mediate toxic AGE-induced facilitation of angiogenesis.

[Effect of Shengqing Capsule on Serum Cholesterol Content and Hepatic Scavenger Receptor Class B of Rats with Cholesterol Calculus].

Objective To observe the effect of Shengqing Capsule (SC) on serum contents of TC, LDL-C, and HDL-C, hepatic scavenger receptor B I (SRB I ) , and CD36 in rats with cholesterol cal- culus. Methods Totally 80 mice were divided into 4 groups according to random number table, i.e., the normal group, the model group, the Western medicine (WM) group, and the Chinese medicine (CM) group, 20 in each group. Mice in the normal group were fed with common forage, while mice in the other 3 groups were fed with lithogenic diet. Mice in the CM group and the WM group were fed with SC (at the daily dose of 0.35 g/kg) and Ursodeoxycholic Acid Tablet (UDCA, at the daily dose of 39. 55 mg/kg) re- spectively for 7 weeks. The general condition and gallstone formation rate were observed. Serum contents of TC, LDL-C, and HDL-C, and protein expressions of SBR I and CD36 were detected by oxidase meth- od and Western blot respectively. Results No gallbladder stone formed in the normal group, and gall- stone formed in 15 mice of the model group with gallstone formation rate of 75%. Compared with the nor- mal group, serum contents of TC and LDL-C and protein expressions of SRB I and CD36 increased, HDL-C content decreased in the model group (P <0. 01). The gallstone formation rate was 35% (7 mice) in the WM group and 30% (6 mice) in the CM group, lower than that of the model group (75%; P <0. 05). Contents of TC and LDL-C, and protein expressions of SRB I and CD36 decreased, HDL-C content in- creased in the WM group and the CM group (P <0.01). Compared with the WM group, TC content and protein expressions of SRB I and CD36 decreased in the CM group (P <0.01). Conclusion SC could prevent and treat gallbladder stone possibly through lowering expression levels of SRB I and CD36.

Zinc oxide nanoparticles induce migration and adhesion of monocytes to endothelial cells and accelerate foam cell formation.

Metal oxide nanoparticles are widely used in industry, cosmetics, and biomedicine. However, the effects of exposure to these nanoparticles on the cardiovascular system remain unknown. The present study investigated the effects of nanosized TiO2 and ZnO particles on the migration and adhesion of monocytes, which are essential processes in atherosclerogenesis, using an in vitro set-up of human umbilical vein endothelial cells (HUVECs) and human monocytic leukemia cells (THP-1). We also examined the effects of exposure to nanosized metal oxide particles on macrophage cholesterol uptake and foam cell formation. The 16-hour exposure to ZnO particles increased the level of monocyte chemotactic protein-1 (MCP-1) and induced the migration of THP-1 monocyte mediated by increased MCP-1. Exposure to ZnO particles also induced adhesion of THP-1 cells to HUVECs. Moreover, exposure to ZnO particles, but not TiO2 particles, upregulated the expression of membrane scavenger receptors of modified LDL and increased cholesterol uptake in THP-1 monocytes/macrophages. In the present study, we found that exposure to ZnO particles increased macrophage cholesterol uptake, which was mediated by an upregulation of membrane scavenger receptors of modified LDL. These results suggest that nanosized ZnO particles could potentially enhance atherosclerogenesis and accelerate foam cell formation.

Transforming growth factor-ß stimulates ß amyloid uptake by microglia through Smad3-dependent mechanisms.

Inflammatory cytokines and ß amyloid (Aß) induce activation of glial cells, leading to both protective and deleterious changes that are relevant for the pathogenesis of Alzheimer disease (AD). We have shown that astrocytes downregulate microglial cell cytotoxic activation through secretion of transforming growth factor-ß (TGFß1), and there is evidence that TGFß1 modifies Aß removal through the modulation of microglia. However, inflammatory activation of microglia is increased and Aß clearance is reduced in AD patients, regardless of the fact that TGFß1 is increased in their nervous system. We propose that changes in TGFß Smad3 signal transduction could modify the regulation mediated by TGFß1. Here we evaluated the participation of the TGFß Smad3 pathway in regulation of the expression pattern of scavenger receptors (SR) and activation of microglia through nitric oxide (NO·) secretion and phagocytosis of Aß. We found that TGFß1 increased SR-A by 2.4-fold and decreased SR-BI expression by 79% at 48 hr, whereas it did not change SR-MARCO or CD36 expression. In addition, we observed a 51% increase of Aß uptake and an 83% decrease of NO· production induced by lipopolysaccharide in microglial cell cultures. Increased expression of SR-A, phagocytosis, and downregulation of NO· by TGFß1 were prevented by the inhibition of the TGFß Smad3 pathway. Our results indicate that the modulation of microglial cell activation by TGFß1, leading to increased clearance of Aß and reduced cytotoxicity, is at least partially mediated by the Smad pathway.

Citrus flavonoid 5-demethylnobiletin suppresses scavenger receptor expression in THP-1 cells and alters lipid homeostasis in HepG2 liver cells.

SCOPE: Nobiletin, a polymethoxyflavone from the peel of citrus fruits, has been reported to inhibit modified LDL uptake in macrophages and enhance hepatic LDL receptor expression and activity. We report the anti-atherogenic effect and mechanism of 5-demethylnobiletin, an auto-hydrolysis product of nobiletin. METHODS AND RESULTS: 5-Demethylnobiletin significantly attenuated phorbol 12-myristate 13-acetate-induced gene expression and activity of scavenger receptors, CD36, scavenger receptor-A and lectin-like oxidized LDL receptor-1. The inhibitory effect is partly associated with the inhibition of protein-kinase C activity and c-Jun NH(2) -terminal kinase 1/2 phosphorylation, thereby inhibiting the activation of activator protein-1 and nuclear factor-κB. 5-Demethylnobiletin treatment also led to reduction of oxidized LDL-induced CD36 mRNA expression and blockade of 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanide perchlorate-modified LDL uptake in THP-1-derived macrophages. In the human hepatoma cell line HepG2, 5-demethylnobiletin significantly induced LDL receptor activity and transcription, at least in part, through steroid-response element-binding protein-2 activation. 5-Demethylnobiletin also decreased the mRNA expression of acyl CoA:diacylglycerol acyltransferase 2, the key enzyme involved in the hepatic triacylglycerol biosyntheses. CONCLUSION: Current results suggest that 5-demethylnobiletin has diverse anti-atherogenic bioactivities. It is more potent in inhibiting monocyte-to-macrophage differentiation and foam cell formation than its permethoxylated counterpart, nobiletin. It exhibits similar hypolipidemic activity as nobiletin and both can enhance LDL receptor gene expression and activity and decreased acyl CoA:diacylglycerol acyltransferase 2 expression.

FTY720 stimulates 27-hydroxycholesterol production and confers atheroprotective effects in human primary macrophages.

RATIONALE: The synthetic sphingosine analog FTY720 is undergoing clinical trials as an immunomodulatory compound, acting primarily via sphingosine 1-phosphate receptor activation. Sphingolipid and cholesterol homeostasis are closely connected but whether FTY720 affects atherogenesis in humans is not known. OBJECTIVE: We examined the effects of FTY720 on the processing of scavenged lipoprotein cholesterol in human primary monocyte-derived macrophages. METHODS AND RESULTS: FTY720 did not affect cholesterol uptake but inhibited its delivery to the endoplasmic reticulum, reducing cellular free cholesterol cytotoxicity. This was accompanied by increased levels of Niemann-Pick C1 protein (NPC1) and ATP-binding cassette transporter (ABC)A1 proteins and increased efflux of endosomal cholesterol to apolipoprotein A-I. These effects were not dependent on sphingosine 1-phosphate receptor activation. Instead, FTY720 stimulated the production of 27-hydroxycholesterol, an endogenous ligand of the liver X receptor, leading to liver X receptor-induced upregulation of ABCA1. Fluorescently labeled FTY720 was targeted to late endosomes, and the FTY720-induced upregulation of ABCA1 was NPC1-dependent, but the endosomal exit of FTY720 itself was not. CONCLUSIONS: We conclude that FTY720 decreases cholesterol toxicity in primary human macrophages by reducing the delivery of scavenged lipoprotein cholesterol to the endoplasmic reticulum and facilitating its release to physiological extracellular acceptors. Furthermore, FTY720 stimulates 27-hydroxycholesterol production, providing an explanation for the atheroprotective effects and identifying a novel mechanism by which FTY720 modulates signaling.

The administration of demethyl fruticulin A from Salvia corrugata to mammalian cells lines induces "anoikis", a special form of apoptosis.

Recently demethyl fruticulin A was identified as the major diterpenoid component of the exudates produced by the trichomes of Salvia corrugata leafs. Given the documented apoptotic effects of some of the other known components of the exudates from Salvia species, we assessed if demethyl fruticulin A, once administered to mammalian cells, was involved in the onset of apoptosis and if its biological effects were exerted through the participation of a scavenger membrane receptor, CD36. Three model cell lines were chosen, one of which lacking CD36 expression. Functional availability of the receptor, or its transcriptional rate, were blocked/reduced with a specific antibody or by the administration of vitamin E. Immunodetection of cell cytoskeletal components and tunel analysis revealed that demethyl fruticulin A triggers the onset of anoikis, a special form of apoptosis induced by cell detachment from the substrate. Impairment of CD36 availability/transcription confirmed the receptor partial involvement in the intake of the substance and in anoikis, as also sustained by FACS analysis and by the downregulation of p95, a marker of anoikis, upon blockade of CD36 transcription. However, experiments with CD36-deficient cells suggested that alternate pathways, still to be determined, may take part in the biological effects exerted by demethyl fruticulin A.

Non-hybridization saturable mechanisms play a role in the uptake of (68)Ga-Labeled LNA-DNA mixmer antisense oligonucleotides in rats.

Oligonucleotides (ODN) are key molecules for the aim of preventing translation of a gene product or monitoring gene expression in tissues. However, multiple methodological and biological hurdles need to be solved before in vivo application in humans will be possible. For positron emission tomography (PET) investigations, a 20-mer DNA-locked nucleic acid (LNA) mixmer ODN specific for rat chromogranin-A mRNA was labeled with (68)Ga and its uptake was examined in vivo in rats with and without blocking of scavenger receptors by polyribonucleotides. In addition, uptake studies of (68)Ga-LNA were performed with respect to time and concentration in human and rat cell lines. The human cell lines did not express the target mRNA. Both polyinosinic acid (poly-I) and polyadenylic acid (poly-A) reduced the uptake in rat tissues and in human cell lines. Poly-I was found to be more effective in the liver whereas poly-A was more effective in the kidney. In addition, the blockade by poly-I was statistically significant in the pancreas, adrenal gland, bone marrow, intestine, testis, urinary bladder, muscle, parotid gland, and heart, whereas poly-A also caused significant reduction in pancreas, adrenal gland, and bone marrow but not as much as in kidney. Cell culture study showed a 2-phase dose-dependent uptake characteristic with a saturable and a passive diffusion-like phase; however, these 2 phases were not so well expressed in the rat cell line. The results suggest that scavenger receptors or other saturable processes unrelated to hybridization may be involved in the tissue uptake of (68)Ga-LNA and in the clearance of antisense ODN through the liver, kidney, spleen, and bone marrow. The fact that these processes may be sequence-dependent suggests that proof of in vivo hybridization through imaging may not be obtained by only comparing sense and antisense sequences and proving dose-dependency.

Association of scavenger receptors in adipose tissue with insulin resistance in nondiabetic humans.

OBJECTIVE: Scavenger receptors play crucial roles in the pathogenesis of atherosclerosis, but their role in insulin resistance has not been explored. We hypothesized that scavenger receptors are present in human adipose tissue resident macrophages, and their gene expression is regulated by adiponectin and thaizolidinediones. METHODS AND RESULTS: The gene expression of scavenger receptors including scavenger receptor-A (SRA), CD36, and lectin-like oxidized LDL receptor-1 (LOX-1) were studied in subcutaneous adipose tissue of nondiabetic subjects and in vitro. Adipose tissue SRA expression was independently associated with insulin resistance. Pioglitazone downregulated SRA gene expression in adipose tissue of subjects with impaired glucose tolerance and decreased LOX-1 mRNA in vitro. Macrophage LOX-1 expression was decreased when macrophages were cocultured with adipocytes or when exposed to adipocyte conditioned medium. Adding adiponectin neutralizing antibody resulted in a 2-fold increase in LOX-1 gene expression demonstrating that adiponectin regulates LOX-1 expression. CONCLUSIONS: Adipose tissue scavenger receptors are strongly associated with insulin resistance. Pioglitazone and adiponectin regulate gene expression of SRA and LOX-1, and this may have clinical implications in arresting the untoward sequalae of insulin resistance and diabetes, including accelerated atherosclerosis.

Ascorbic acid pre-treated quartz stimulates TNF-alpha release in RAW 264.7 murine macrophages through ROS production and membrane lipid peroxidation.

BACKGROUND: Inhalation of crystalline silica induces a pulmonary fibrotic degeneration called silicosis caused by the inability of alveolar macrophages to dissolve the crystalline structure of phagocytosed quartz particles. Ascorbic acid is capable of partially dissolving quartz crystals, leading to an increase of soluble silica concentration and to the generation of new radical sites on the quartz surface. The reaction is specific for the crystalline forms of silica. It has been already demonstrated an increased cytotoxicity and stronger induction of pro-inflammatory cyclooxygenase-2 (COX-2) by ascorbic acid pre-treated quartz (QA) compared to untreated quartz (Q) in the murine macrophage cell line RAW 264.7. METHODS: Taking advantage of the enhanced macrophage response to QA as compared to Q particles, we investigated the first steps of cell activation and the contribution of early signals generated directly from the plasma membrane to the production of TNF-alpha, a cytokine that activates both inflammatory and fibrogenic pathways. RESULTS: Here we demonstrate that TNF-alpha mRNA synthesis and protein secretion are significantly increased in RAW 264.7 macrophages challenged with QA as compared to Q particles, and that the enhanced response is due to an increase of intracellular ROS. Plasma membrane-particle contact, in the absence of phagocytosis, is sufficient to trigger TNF-alpha production through a mechanism involving membrane lipid peroxidation and this appears to be even more detrimental to macrophage survival than particle phagocytosis itself. CONCLUSION: Taken together these data suggest that an impairment of pulmonary macrophage phagocytosis, i.e. in the case of alcoholic subjects, could potentiate lung disease in silica-exposed individuals.

New stemona alkaloids from the roots of Stemona sessilifolia.

From the roots of Stemona sessilifolia, three new stemona-type alkaloids, namely stemosessifoine (1), isooxymaistemonine (2), and isomaistemonine (3), along with eight known alkaloids (bisdehydrostemoninine, isobisdehydrostemoninine, tuberostemonine, bisdehydrotuberostemonine, bisdehydrostemoninine, isobisdehydrostemoninine, stemoninine, and protostemonine), were isolated. Their structures were determined on the basis of extensive 2D-NMR spectroscopic-data analysis and by comparison with reported values in the literature. Compound 1 is a structurally unprecedented alkaloid, and it is depicted to be bioconverted from tuberostemonine as the precursor. Isooxymaistemonine (2) showed a positive effect on the human high-density lipoprotein (HDL) receptor gene CD36 and LIMP II analogous-1 (CLA-1) at the dosage of 10 microg/ml.

Toxicity of lunar and martian dust simulants to alveolar macrophages isolated from human volunteers.

NASA is planning to build a habitat on the Moon and use the Moon as a stepping stone to Mars. JSC-1, an Arizona volcanic ash that has mineral properties similar to those of lunar soil, is used to produce lunar environments for instrument and equipment testing. NASA is concerned about potential health risks to workers exposed to these fine dusts in test facilities. The potential toxicity of JSC-1 lunar soil simulant and a Martian soil simulant (JSC-Mars-1, a Hawaiian volcanic ash) was evaluated using human alveolar macrophages (HAM) isolated from volunteers; titanium dioxide and quartz were used as reference dusts. This investigation is a prerequisite to studies of actual lunar dust. HAM were treated in vitro with these test dusts for 24 h; assays of cell viability and apoptosis showed that JSC-1 and TiO2 were comparable, and more toxic than saline control but less toxic than quartz. HAM treated with JSC-1 or JSC-Mars 1 showed a dose-dependent increase in cytotoxicity. To elucidate the mechanism by which these dusts induce apoptosis, we investigated the involvement of scavenger receptors (SR). Pretreatment of cells with polyinosinic acid, an SR blocker, significantly inhibited both apoptosis and necrosis. These results suggest HAM cytotoxicity may be initiated by interaction of the dust particles with SR. Besides being cytotoxic, silica is known to induce shifting of HAM phenotypes to an immune active status. The immunomodulatory effect of the dust simulants was investigated. Treatment of HAM with either simulant caused preferential damage to the suppressor macrophage subpopulation, leading to a net increase in the ratio of activator (RFD1+) to suppressor (RFD1+7+) macrophages, an effect similar to that of treatment with silica. It is recommended that appropriate precautions be used to minimize exposure to these fine dusts in large-scale engineering applications.

In vivo immunomodulatory effects of aqueous extracts of Larrea divaricata Cav.

Several medicinal plants are considered immunomodulatory as they display a variety of anti-inflammatory, antimicrobial and antitumoral effects. Larrea divaricata Cav. (jarilla) (Zygophyllaceae) is a plant widely used in popular medicine to treat tumors, infections, and inflammatory diseases. So far, the immunostimulating activities of Larrea divaricata have not been studied in vivo. In this work, we used healthy mice to assess the immunomodulatory potential of aqueous extracts of Larrea divaricata Cav. We found that Decoction (D) and Infusion (I) from Larrea divaricata Cav showed any acute hepatotoxic activity. Only D at 0.5 mg/kg increased the carrageenan-induced inflammation. Macrophages harvested from treated mice showed no signs of apoptosis. These cells showed a significant increase in NO and TNF-alpha release and exhibited the strongest expression of iNOS. Decoction also increased the phagocytosis of zymosan and the binding of LPS-FITC. The expression of CD14, TLR4 and CR3 was lower in macrophages of mice treated than in controls. Thus, Larrea divaricata was able to prime Mphi in vivo and to induce full activation in vitro. Our finding contribute to characterize the biological activity of Larrea divaricata and to understand the ability of these extracts to enhance immune responses.

Effects of new combinative antioxidant FeAOX-6 and alpha-tocotrienol on macrophage atherogenesis-related functions.

Pivotal role in atherogenesis is played by macrophages, which are early site for lipid accumulation and mediate the inflammatory and immune response in the intima. Epidemiological evidence indicates that natural antioxidants reduce the risk of heart disease, but, so far, supplementation studies have failed to confirm any protective effects of these compounds against cardiovascular disease. This study evaluated the effects of the natural antioxidant alpha-tocotrienol and of the newly designed compound, FeAOX-6, which combines antioxidant structural features of both tocopherols and carotenoids into a single molecule, on macrophage functions involved in foam cell formation. FeAOX-6 or alpha-tocotrienol induce a strong dose-dependent reduction of cholesterol and reduce cholesterol accumulation in human macrophages. The extent of the reduction found with alpha-tocotrienol was greater than that induced by FeAOX-6 and did not correlate with their respective antioxidant capacities. Treatment of HMDM with alpha-tocotrienol or FeAOX-6 enhanced also tumor necrosis factor-alpha secretion. These results are consistent with a reduction in scavenger receptor activity, but we found that antioxidant treatment did not affect cholesterol uptake from modified LDL. The effects on release on pro-inflammatory prostanoid precursors, PGE(2) and cytokine suggest a variety of metabolic responses that are both dependent on antioxidant compounds and macrophages activation status.

A murine scavenger receptor MARCO recognizes polystyrene nanoparticles.

Recent toxicological studies indicate that nanoparticles or ultrafine particles (< 100 nm) are more toxic than fine particles (< 2 microm) because of their greater surface area. It is well known that alveolar macrophages play an important role in the first defense against various environmental particles and microorganisms. This is accomplished by binding to a macrophage receptor with collagenous structure (MARCO), one of several scavenger-type receptors expressed on the cell surface of macrophages. MARCO has been shown to mediate the ingestion of unopsonized environmental particles such as TiO(2) and Fe(2)O(3) (1.3 microm in diameter). However, very little is known about the cellular uptake of nanoparticles. In the present study, we investigated whether MARCO mediates the uptake of nanoparticles by using fluorescent-tagged polystyrene particles (20 nm, 200 nm, and 1 microm in diameter). COS-7 cells were transfected with either MARCO cDNA or an empty vector, and the association of the particles with the cells were observed by fluorescence microscopy and atomic force microscopy. MARCO-transfected cells associated with all three sizes of particles in a time-dependent manner, while no obvious binding of particles occurred after 5 h to the empty vector-transfected cells. The uptake of particles by MARCO-transfected cells was partially inhibited by polyG. These results suggest that macrophages associate with nanoparticles (20 nm) at least in part through MARCO and that MARCO plays a role in clearing nanoparticles which can deposit in the alveolar region.

The strange case of Dr HDL and Mr HDL: does a NO's story illuminate the mystery of HDL's dark side uncovered by Dr HDL's drug targeting CETP?

Recently, the first large-scale morbidity and mortality trial (ILLUMINATE) to evaluate the cardiovascular end points of a CETP inhibitor (torcetrapib) has been prematurely stopped because the mortality was significantly increased in the treated group. Why torcetrapib caused excess death is not known. Based on the fact that HDL interacts with endothelial nitric oxyde synthase (eNOS) and nitric oxide (NO) secretion, which partly controlled blood pressure and than torcetrapib could increase blood pressure among some patients, we hypothesize that CETP inhibition could have significantly inhibit eNOS. CETP inhibition would have enlarged HDL size resulting in a deficit in the interaction between HDL and the Scavenger Receptor class B type I (SR-BI), which is an important link between HDL and eNOS activation. We suggest than the deficit in NO secretion would have been sufficient among all patients to induce a destabilization of the plaques of atheroma, but could have induced a pathogenic increase in blood pressure only in patients whose eNOS activity was naturally weak due to genetic polymorphisms of this enzyme. We also hypothesize that the increase in HDL levels, induced by CETP inhibition, coupled with the capacity of HDL to induce endothelin-1 secretion would have aggravated the cardiovascular risks under this CETP inhibitor treatment.

Anti-tumor necrosis factor-alpha antibody treatment reduces serum CXCL16 levels in patients with rheumatoid arthritis.

The aim of this study was to analyze the change of serum chemokins levels of CXCL16, CX3CL1/Fractalkine, and CXCL10/interferon-gamma inducible protein-10 (IP-10) with rheumatoid arthritis (RA), by infliximab treatment. The effects of infliximab treatment were studied in 23 patients with RA, over a period of 30 weeks. The serum levels of CXCL16, Fractalkine, and IP-10, were measured at the baseline, just before initial treatment, and at 14 and 30 weeks after the initial treatment, with infliximab by ELISA. The higher levels of serum CXCL16 in the RA patients before treatment with infliximab significantly decreased at 14 and 30 weeks after the initial treatment with infliximab, but the serum Fractalkine and IP-10 levels did not decrease significantly. Infliximab treatment significantly lowered the serum levels of CXCL16 in patients with RA. CXCL16 is one of the crucial chemokines regulated by infliximab treatment.

[Lox-1--an actor in cardiovascular disease?]. / LOX-1--en aktør ved hjerte- og karsykdommer?

BACKGROUND: Among risk factors such as smoking, hypertension and LDL cholesterol, oxidized LDL (ox-LDL) has emerged as a new and interesting factor. Scavenger receptors are a group of cell-surface receptors located on various cell types within the vessel wall with special affinity for ox-LDL. Of all the scavenger receptors involved in coronary heart disease, the lectin-like oxidized low-density lipoprotein receptor (LOX-1) is probably the most important. MATERIAL AND METHODS: This article provides a general overview of the scavenger receptors, with special emphasis on LOX-1 and its role in hypertension, heart failure, atherosclerotic heart disease and diabetes mellitus, based on the literature and our own published data. RESULTS AND INTERPRETATION: LOX-1 is located in various cell types within atherosclerotic plaque, in humans as well in animals, and it accumulates during the progression of the plaque. The receptor is highly expressed in hypertension, hyperhomocysteinaemia and diabetes mellitus. Data indicate that there is a complex interaction between LOX-1 and a number of different processes, such as inflammation, lipid accumulation and oxidative stress. In addition, LOX-1 seems to have therapeutic potential, and a prospective treatment aiming to reduce the level of LOX-1 may be important in the development of atherosclerotic disease, such as coronary heart disease.

Fucoidan induces nitric oxide production via p38 mitogen-activated protein kinase and NF-kappaB-dependent signaling pathways through macrophage scavenger receptors.

It has been reported that ligands of the macrophage scavenger receptor (MSR) induce a range of cellular responses including urokinase-type plasminogen activator and the production of inflammatory cytokines. Although nitric oxide (NO) is an important regulatory molecule in physiological functions such as vascular homeostasis, neurotransmission, and host defense, the effect of MSR ligands on NO production from macrophages was unknown. Here, we demonstrate that the MSR ligand, fucoidan, but neither oxidized low-density lipoprotein, acetylated LDL, maleylated bovine serum albumin nor dextran sulfate induces activation of inducible nitric oxide synthase (iNOS) promoter or NO production in RAW264.7 cells. Furthermore, we investigated the molecular mechanism by which fucoidan induces iNOS promoter activation. Using different inhibitors, we showed that the stimulation of fucoidan was mediated by both the p38 mitogen-activated protein kinase and the NF-kappaB-dependent pathways. Although these two pathways were independent, heat shock protein 90 (HSP90) played a significant role in both pathways. Our previous study showed that HSP90 directly interacts with the cytoplasmic domain of MSR. These results provide the evidence that HSP90 bound to the cytoplasmic domain of MSR is implicated in MSR-mediated signal transduction. Moreover, fucoidan-induced NO production by peritoneal macrophages from MSR-knockout (MSR-/-) mice significantly decreases compared with those from wild-type mice. This is the first indication that MSR transduces the signal of fucoidan to iNOS gene expression.

Synthetic retinoid Am80 reduces scavenger receptor expression and atherosclerosis in mice by inhibiting IL-6.

BACKGROUND: Macrophage scavenger receptors facilitate the uptake of modified low-density lipoprotein (LDL), formation of foam cells, and development of atherosclerosis. Given that proinflammatory cytokines, including IL-6, can modulate the macrophage foaming process, the aim of the present study was to determine whether the synthetic retinoic acid receptor-alpha/beta-specific agonist Am80, which is also an IL-6 inhibitor, can modulate macrophage lipid accumulation and foam cell formation. METHODS AND RESULTS: Am80 suppressed IL-6 production induced by 12-myristate 13-acetate (PMA) or angiotensin II in mouse Raw264 macrophages. It also suppressed expression of the 2 major scavenger receptors (scavenger receptor-A [SR-A] and CD36), in part by inhibiting IL-6, and inhibited macrophage foam cell formation. Systemic administration of Am80 led to reductions in the areas of atherosclerotic lesions and foam cell accumulation in the aortas of apolipoprotein E (apoE)-deficient mice and reduced serum concentrations of IL-6 and IL-1beta without affecting body weights, serum lipid profiles or IL-10 levels. CONCLUSIONS: Am80 suppresses scavenger receptor expression and macrophage foam cell formation in vitro and prevents atherogenesis in apoE-deficient mice in vivo. This suggests Am80 is a novel candidate agent that could be highly useful in the prevention and treatment of atherosclerosis.