Scavenger Receptor Gene Research Articles

Cloning, Expression Feature, and Tissue Location of BmSCRBQ1, a Class B Scavenger Receptor in Bombyx mori (L.)

Abstract Class B scavenger receptors can combine with various kinds of ligands and are involved in lipid metabolism. They play an important role in a series of physiological processes, such as atherosclerosis formation or inhibition, congenital immune defense, apoptotic cell clearance, carotenoid transport, and pheromone transduction. In this study, based on a whole-genome database of the silkworm (Bombyx mori (L.)), the full-length CDS of BmSCRBQ1, a class B scavenger receptor gene, was cloned. BmSCRBQ1 consists of 10 exons and 9 introns, with an open reading frame of 1,482 bp encoding 493 amino acids. BmSCRBQ1 mRNA and protein were expressed in most tissues of larval B. mori strain Dazao and the silkworm cell lines BmN and BmE, suggesting that BmSCRBQ1 may have certain ubiquitous functions. Immunohistochemical staining showed that BmSCRBQ1 protein is located in the constitutive membranes or cell membranes of the testes, ovaries, fat body, blood cells, and the middle silk gland of larval B. mori Dazao, indicating that its function could be related to lipid metabolism; the binding, transport, and phagocytosis of exogenous materials; and signal transduction in these tissue types.

Class A Scavenger Receptor Deficiency Exacerbates Lung Tumorigenesis by Cultivating a Procarcinogenic Microenvironment in Humans and Mice

Genetic alterations on 8p22 have been implicated in multiple cancers, including lung cancer. In this region, genetic variants of the class A scavenger receptor (SR-A) gene have been associated with prostate cancer risk and have been highlighted as a potential susceptibility gene of cancer. To determine whether common polymorphisms in the SR-A gene are associated with human lung cancer risk and to clarify the role of SR-A in lung carcinogenesis. The relationship of three potentially functional polymorphisms (T-365C, T+25C, and Ala275Pro) in the SR-A gene with lung cancer risk was evaluated in 1287 lung cancer case subjects and 1261 control subjects from the Chinese population. At the same time, SR-A null mice were used to investigate its role in lung cancer development. The T+25C polymorphism was independently associated with lung cancer risk and significantly correlated with decreased expression of SR-A. The decreased SR-A expression was also found in tumor tissues as compared with normal tissues. Depletion of SR-A boosted the growth and angiogenesis of implanted Lewis lung carcinoma in mice. The cancer-suppressing capability of SR-A was attributable to its expression in bone marrow-derived cells as evidenced by bone marrow transplantation. Further analysis revealed augmented expression of proangiogenic factors including matrix metalloproteinase-9 (MMP9) in SR-A-deficient mice, indicative of a more procarcinogenic microenvironment. Last, zoledronate, an MMP9 inhibitor, abrogated acceleration of tumor growth conferred by SR-A loss-of-function. Evidence from the population study and mouse model strongly indicates that SR-A may function as a tumor modulator to inhibit lung cancer growth through affecting the tumor microenvironment.

Scavenger receptors: a key player in cardiovascular diseases.

Abstract The scavenger receptor (SR) super family consists of integral membrane glycoproteins that are involved in recognition of polyanionic structures of either endogenous (e.g., oxidized low-density lipoprotein) or exogenous (e.g., bacterial lipopolysaccharides) origin. SRs are structurally diverse and can be classified into seven different classes (A-G) based on the multidomain structure of the individual members. SRs are present on various types of tissues, such as vascular, adipose, and steroidogenic tissues. In addition to modified lipoprotein uptake, these proteins are also known to regulate apoptotic cell clearance, initiate signal transduction, and serve as pattern recognition receptors for pathogens. Different SRs are involved in many physiological and pathological processes; more importantly, the function of SRs is highly implicated in the initiation and progression of atherosclerotic plaque. Targeting the SR gene products that mediate the response to and uptake of modified lipids holds great promise in the prevention of cardiovascular diseases. Inhibition of SR expression using a combined gene therapy and RNA interference strategy also appears to be an option for long-term therapy. The present review focuses on the involvement of SRs in atherosclerosis, thrombosis, and other cardiovascular diseases. Moreover, the role of SRs is not restricted to vascular lesions; it is also implicated in a number of different cellular functions.

Genetic variants of the class A scavenger receptor gene are associated with coronary artery disease in Chinese

The class A scavenger receptor, encoded by the macrophage scavenger receptor 1 (MSR1) gene, is a pattern recognition receptor (PPR) primarily expressed in macrophages. It has been reported that genetic polymorphisms of MSR1 are significantly associated with the number of diseased vessels and coronary artery narrowing greater than 20% in Caucasians. However, whether it links genetically to coronary artery disease (CAD) in Chinese is not defined. Here, we performed an independent case-control study in a Chinese population consisting of 402 CAD cases and 400 controls by genotyping ten single nucleotide polymorphisms (SNPs) of MSR1. We found that rs416748 and rs13306541 were significantly associated with an increased risk of CAD with per allele odds ratio (OR) of 1.56 [95% confidence interval (CI) = 1.28–1.90; P < 0.001] and 1.70 (95% CI = 1.27–2.27; P < 0.001), respectively. Our results indicate that genetic variants of MSR1 may serve as predictive markers for the risk of CAD in combination with traditional risk factors of CAD in Chinese population.

Pteromalus puparum venom impairs host cellular immune responses by decreasing expression of its scavenger receptor gene

Insect host/parasitoid interactions are co-evolved systems in which host defenses are balanced by parasitoid mechanisms to disable or hide from host immune effectors. Although there is a rich literature on these systems, parasitoid immune-disabling mechanisms have not been fully elucidated. Here we report on a newly discovered immune-disabling mechanism in the Pieris rapae/ Pteromalus puparum host/parasitoid system. Because venom injections and parasitization suppresses host phagocytosis, we turned attention to the P. rapae scavenger receptor (Pr-SR), posing the hypothesis that P. puparum venom suppresses expression of the host Pr-SR gene. To test our hypothesis, we cloned a full-length cDNA of the Pr-SR. Multiple sequences alignment showed the deduced amino acid sequence of Pr-SR is similar to scavenger receptors of other lepidopterans. Bacterial and bead injections induced Pr-SR mRNA and protein expression, which peaked at 4 h post-bead injection. Venom injection inhibited Pr-SR expression. Pr-SR was specifically expressed in granulocytes compared to plasmatocytes. We localized the Pr-SR protein in cytoplasm and cellular membrane, with no evidence of secretion into host plasma. Double-strand RNA designed to Pr-SR mRNA silenced expression of Pr-SR and significantly impaired host phagocytosis and encapsulation reactions. Venom injections similarly silenced Pr-SR expression during the first 8 h post-treatment, after which the silencing effects gradually abated. We infer from these findings that one mechanism of impairing P. rapae hemocytic immune reactions is by silencing expression of Pr-SR.

Isolation and phenotypic characterization of a multinucleated tartrate-resistant acid phosphatase–positive bone marrow macrophage

Prothrombin (PT) and osteopontin (OPN) promote adhesion of bone-derived tartrate-resistant acid phosphatase (TRAP, Acp5)-positive multinucleated cells differing in size, morphology, and resorptive activity. Here we explored phenotypic and functional differences between these cells. Global-wide and TRAP (Acp5) promoter messenger RNA expression, ability for phagocytosis, macrophage colony-stimulating factor-dependent migration, and in situ localization of these cells were investigated. Gene expression of PT-adherent cells was skewed toward expression of innate immune response, phagocytosis, and scavenger receptor genes. They avidly phagocytosed Staphylococcus aureus and Dextran particles, and their migration on PT was enhanced by macrophage colony-stimulating factor. In contrast, OPN-adherent cells lacked ability to phagocytose particles and their migration on OPN was inhibited by macrophage colony-stimulating factor. They expressed typical osteoclast proteases implicated in bone matrix degradation, such as the collagenases cathepsin K; matrix metalloprotease-2; -9; -13; and -14, consistent with their high bone resorptive activity in vitro. In addition, OPN-adherent cells predominantly expressed the PU.1/MiTF/NFATc1-driven TRAP exon 1C messenger RNA, whereas PT-adherent cells preferably expressed TRAP exon 1B messenger RNA. Furthermore, CD163/cathepsin-K immunohistochemistry demonstrated that PT-adherent cells were predominantly located in the diaphyseal bone marrow compartment, whereas the OPN-adherent cells were attached to cortical and distal metaphyseal trabecular bone surfaces. This study identifies differences in expression of several osteoclast and macrophage genes, as well as functional differences between PT- and OPN-adherent cells. We conclude that the OPN-adherent cells display osteoclast characteristics, especially with regard to expression of matrix-degrading enzymes, whereas the PT-adherent cell might represent a unique TRAP-positive multinucleated bone marrow macrophage implicated in immune recognition and phagocytosis.

The investigation of CD36 scavenger receptor and MSR1 scavenger receptor gene expression level in patients with atherosclerosis

The investigation of CD36 scavenger receptor and MSR1 scavenger receptor gene expression level in patients with atherosclerosis

PU.1 Directly Regulates cdk6 Gene Expression, Linking the Cell Proliferation and Differentiation Programs in Erythroid Cells

Cell proliferation and differentiation are highly coordinated processes during normal development. Most leukemia cells are blocked from undergoing terminal differentiation and also exhibit uncontrolled proliferation. Dysregulated expression of transcription factor PU.1 is strongly associated with Friend virus-induced erythroleukemia. PU.1 inhibits erythroid differentiation by binding to and inhibiting GATA-1. PU.1 also may be involved in controlling proliferation of erythroid cells. We reported previously that the G(1) phase-specific cyclin-dependent kinase 6 (CDK6) also blocks erythroid differentiation. We now report that PU.1 directly stimulates transcription of the cdk6 gene in both normal erythroid progenitors and erythroleukemia cells, as well as in macrophages. We propose that PU.1 coordinates proliferation and differentiation in immature erythroid cells by inhibiting the GATA-1-mediated gene expression program and also by regulating expression of genes that control progression through the G(1) phase of the cell cycle, the period during which the decision to differentiate is made.

Divergence of Macrophage Phagocytic and Antimicrobial Programs in Leprosy

Effective innate immunity against many microbial pathogens requires macrophage programs that upregulate phagocytosis and direct antimicrobial pathways, two functions generally assumed to be coordinately regulated. We investigated the regulation of these key functions in human blood-derived macrophages. Interleukin-10 (IL-10) induced the phagocytic pathway, including the C-type lectin CD209 and scavenger receptors, resulting in phagocytosis of mycobacteria and oxidized low-density lipoprotein. IL-15 induced the vitamin D-dependent antimicrobial pathway and CD209, yet the cells were less phagocytic. The differential regulation of macrophage functional programs was confirmed by analysis of leprosy lesions: the macrophage phagocytosis pathway was prominent in the clinically progressive, multibacillary form of the disease, whereas the vitamin D-dependent antimicrobial pathway predominated in the self-limited form and in patients undergoing reversal reactions from the multibacillary to the self-limited form. These data indicate that macrophage programs for phagocytosis and antimicrobial responses are distinct and differentially regulated in innate immunity to bacterial infections.

P.3.c.055 The incidence of metabolic syndrome and its reversibility in patients with psychotic disorders followed for one year

The variability of the Class B Type I Scavenger Receptor (SR-BI) gene in human populations and the relation of its variants to blood lipids was investigated in a random sample of 1756 untreated adult residents of Geneva, Switzerland, during 1999–2000. A three-step study approach yielded the following results: (1) resequencing the gene’s exons and flanking regions in 95 subjects identified four common single nucleotide polymorphisms (SNPs with rare allele frequency >3%); (2) association study of the four common SNPs in subjects with extreme HDL-cholesterol (HDL-C) and LDL-C phenotypes (186 “atherogenic cases” and 185 “non-atherogenic controls”) showed that the synonymous exon 8 C-T (allelic frequency 48%) polymorphism, A350A, was associated with atheroprotection in men (odds ratios (OR)=0.36, 95% confidence intervals (CI)=0.15–0.90, P<0.03), but not in women (2.09, 0.79–5.49, P=0.14);and (3) population clinical effects of A350A genotypes assessed in all 1756 subjects, showed that the case–control study findings reflected a protective HDL-C effect in men (CC: 1.17 mmol/L, CT: 1.22 mmol/L, and TT: 1.24 mmol/L, trend P=0.0062) and a deleterious LDL-C effect in women (CC: 3.58 mmol/L, CT: 3.72 mmol/L, and TT: 3.79 mmol/L, trend P=0.014). The allelic frequencies of the common SR-BI variants appear to be very similar in European and North American populations. The HDL-C effect increased with age. SR-BI A350A appears to have gender-specific and age-related effects on cholesterol transport lipoproteins.

Autoimmunity in atherosclerosis: a protective response losing control?

Atherosclerosis is a chronic inflammatory disease characterized by accumulation of oxidized lipoproteins, increased cell death and hypertrophic degeneration of the arterial intima. The disease process is associated with local formation of modified self antigens that are targeted by both innate and adaptive immune responses. Although it remains to be firmly established it is likely that these autoimmune responses initially have a beneficial effect facilitating the removal of potentially harmful rest products from oxidized LDL and dying cells. However, studies performed on hypercholesterolaemic mice deficient in different components of the immune system uniformly suggest that the net effect of immune activation is pro-atherogenic and that atherosclerosis, at least to some extent, should be regarded as an autoimmune disease. These observations point to the possibility of developing new treatments for atherosclerosis based on modulation of immune responses against plaque antigens, an approach presently tested clinically for several other chronic inflammatory diseases with autoimmune components. Pilot studies in animals have provided promising results for both parental and oral vaccines based on oxidized LDL antigens. The time when this concept is ready for clinical testing is rapidly approaching but it will be important not to underestimate the difficulties that will be encountered in transferring the promising results from experimental animals into humans.

Class A macrophage scavenger receptor gene expression levels in peripheral blood mononuclear cells specifically increase in patients with acute coronary syndrome

Objective Morbidity and mortality rates are still high among patients with acute coronary syndrome (ACS); moreover, it is clinically difficult to determine precisely which patients will progress satisfactorily. Unstable plaque is characterized by an increased number of activated inflammatory cells, including macrophages and lymphocytes, and an increased release of numerous inflammatory mediators and proteolytic enzymes. Mononuclear cells consist of monocytes/macrophages and lymphocytes and are able to be experimentally isolated. We searched for a specific risk factor for ACS in the peripheral blood mononuclear cells (PBMCs). Methods and results We examined the expression of 12,625 genes in PBMCs utilizing a gene chip microarray system in ACS patients in acute and chronic stable phases. The gene expression profiles revealed that class A macrophage scavenger receptors (SR-A), among the immune response factors and the receptor activity markers, were the most strongly increased in the acute phase. We examined SR-A gene expression levels of PBMCs using real time RT-PCR in 122 consecutive patients: 32 ACS patients; 41 stable angina patients; and, 49 control subjects. The SR-A gene expression levels of the PBMCs were highest in the ACS patients ( p < 0.0001). The occurrence of a reattack of a cardiovascular event was significantly lower in the low SR-A group than in the high SR-A group ( p < 0.001). Conclusion SR-A gene expression level in the PBMCs specifically increases in patients with ACS, and provides a predictive marker for a reattack of a cardiovascular event.

Zerumbone Suppresses Phorbol Ester-Induced Expression of Multiple Scavenger Receptor Genes in THP-1 Human Monocytic Cells

Unregulated uptake of oxidized low-density lipoproteins (ox-LDL) via macrophage scavenger receptors (SRs), such as lectin-like ox-LDL receptor-1 (LOX-1), is a key event in atherosclerosis. In the present study, we used differentiated Caco-2 cells as a model of the human small intestine to evaluate the suppressive effects of 16 traditional food items selected from Okinawa on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced LOX-1 mRNA expression in THP-1 human monocyte-like cells. Three Zingiberaceae plants, Curcuma aromatica Salisbury, Curcuma longa L., and Zingiber zerumbet Smith, markedly suppressed that expression. When added to the apical sides of Caco-2 monolayers, zerumbone, a sesquiterpene from Z. zerumbet Smith, was found to permeate into the basolateral medium as an intact structure in a time-dependent manner. alpha-Humulene, a structural analog of zerumbone lacking the alpha,beta-unsaturated carbonyl group, did not suppress LOX-1 mRNA expression, indicating that its electrophilic moiety might play pivotal roles in its activities. Further, zerumbone attenuated the expression of SR-A, SR-PSOX, and CD36, but not that of CD68 or CLA-1, leading to a blockade of DiI-acLDL uptake, while it also inhibited the transcriptional activities of activator protein-1 and nuclear factor-kappaB. Together, our results indicate that zerumbone is a potential phytochemical for regulating atherosclerosis with reasonable action mechanisms.

Suppressive effects of demethylated metabolites of nobiletin on phorbol ester‐induced expression of scavenger receptor genes in THP‐1 human monocytic cells

Unregulated uptake of oxidized low-density lipoproteins (ox-LDL) via macrophage scavenger receptors (SRs) is a key event in atherosclerosis. We previously reported that nobiletin (NOB), a citrus polymethoxylated flavone, markedly reduced 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced SRs and adhesion molecules mRNA expression and blockade of DiI-acLDL uptake in THP-1 human monocyte-like cells. In this study, we examined the effects of NOB metabolites, 3'-hydroxy-5,6,7,8,4'-pentamethoxyflavone (3'-demethyl-NOB), 4'-hydroxy-5,6,7,8,3'-pentamethoxyflavone (4'-demethyl-NOB) and 3', 4'-dihydroxy-5,6,7,8,-tetramethoxyflavone (3', 4'-didemethyl-NOB) and NOB analog, tangeretin, on SRs and adhesion molecules mRNA expression. 3'-Demethyl-NOB significantly suppressed CD36 expression, moreover, 4'-demethyl- and 3', 4'-didemethyl-NOB significantly suppressed TPA-induced expression of SR-A and LOX-1. Further, the suppressive effects of 4'-demethyl- and 3', 4'-didemethyl-NOB on the expression of CD36 mRNA were greater extent than parent NOB. The inhibitory effects of the metabolites toward TPA-induced SR mRNA expression are partly associated with the suppression of AP-1 and NF-kappaB transcriptional activities. Together, our results suggest that metabolites of NOB, such as 4'-demethyl- and 3', 4'-didemethyl-NOB, have comparable or higher potentials to attenuate SR expression than NOB.

Nobiletin, a citrus flavonoid, suppresses phorbol ester-induced expression of multiple scavenger receptor genes in THP-1 human monocytic cells

Unregulated uptake of oxidized low-density lipoproteins (ox-LDL) via macrophage scavenger receptors (SRs) such as lectin-like ox-LDL receptor-1 (LOX-1) is a key event in atherosclerosis. In this study, we examined the effects of five selected food phytochemicals on 12- O-tetradecanoylphorbol-13-acetate (TPA)-induced LOX-1 mRNA expression in THP-1 human monocyte-like cells. Nobiletin, a citrus polymethoxylated flavone, markedly reduced it in dose- and time-dependent manners. It also suppressed the phosphorylation of extracellular signal-regulated protein kinase (ERK) 1/2, c-Jun NH 2-terminal kinase (JNK) 1/2, and c-Jun (Ser-63), thereby inhibiting the transcriptional activity of activator protein-1. Further nobiletin attenuated expression of SR-A, SR-PSOX, CD36, and CD68, but not CLA-1, mRNA, leading to the blockade of DiI-acLDL uptake. Together, our results suggest that nobiletin is a promising phytochemical for regulating atherosclerosis with reasonable action mechanisms.

Novel scavenger receptor gene is differentially expressed in the embryonic and adult mouse testis

In an effort to understand the mechanisms that underpin gonadal differentiation at the time of sex determination, we identified a cDNA encoding a putative novel testis expressed scavenger receptor, Tesr. Based on its domain structure, we hypothesize that the function of Tesr is similar to that of other scavenger receptors that play roles in phagocytosis of apoptotic cells, cell-cell adhesion, and defense. Tesr mRNA was detected in fetal mouse gonads of both sexes at 11.5 days post coitum (dpc). From 12.0 dpc, Tesr expression rapidly decreased in the female and was maintained in the male. Expression was seen in embryonic mouse sites other than the testis, such as in brain, eye, head, heart, neural arch, and cartilage primordium. Tesr expression in the newborn testis was faint to undetectable, but it increased from 2 days postpartum (dpp) until 15 dpp and was found in a subset of interstitial cells and in germ and Sertoli cells. Tesr mRNA in the adult mouse testis was observed in Sertoli cells, spermatogonia, spermatocytes, round spermatids, and in a subset of interstitial cells. We conclude that Tesr is differentially expressed in the male vs. female embryonic gonad and is expressed in both the ovary and the testes postnatally after 2 dpp.

Glycoxidized low-density lipoprotein regulates the expression of scavenger receptors in THP-1 macrophages

Low-density lipoprotein (LDL) in patients with diabetes is subject to modification by both oxidation and glycation. In contrast to oxidized LDL, the biological effects of glycoxidized LDL have not been well characterised. In this study, the effects of oxidized, glycated, glycoxidized and oxidized LDL on scavenger receptor gene expressions, and the induction of oxidized LDL uptake and cholesteryl ester accumulation in THP-1 macrophages were compared. Modified LDL was incubated with THP-1 macrophages. Gene expression of scavenger receptor class A (SR-A), CD36 and scavenger receptor class B type I (SR-BI) was determined by quantitative reverse transcriptase PCR (RT-PCR). Glycoxidized LDL was able to significantly induce SR-A and CD36 expression by 3- and 4.5-fold, respectively, in macrophages whereas SR-BI expression was suppressed by glycoxidized LDL, glycated LDL and oxidized LDL. Incubation with glycoxidized LDL enhanced the uptake of DiI-labeled oxidized LDL by macrophages to a greater extent than that of glycated LDL or oxidized LDL. Glycoxidized LDL also induced a significant degree of intracellular cholesteryl ester accumulation. Taken together, our results would suggest that glycoxidized LDL might be an important candidate in the initiation of foam cell formation and might play a significant role in the pathogenesis of atherosclerosis in diabetes mellitus.

Population-based study of SR-BI genetic variation and lipid profile

The variability of the Class B Type I Scavenger Receptor (SR-BI) gene in human populations and the relation of its variants to blood lipids was investigated in a random sample of 1756 untreated adult residents of Geneva, Switzerland, during 1999–2000. A three-step study approach yielded the following results: (1) resequencing the gene’s exons and flanking regions in 95 subjects identified four common single nucleotide polymorphisms (SNPs with rare allele frequency >3%); (2) association study of the four common SNPs in subjects with extreme HDL-cholesterol (HDL-C) and LDL-C phenotypes (186 “atherogenic cases” and 185 “non-atherogenic controls”) showed that the synonymous exon 8 C-T (allelic frequency 48%) polymorphism, A350A, was associated with atheroprotection in men (odds ratios (OR)=0.36, 95% confidence intervals (CI)=0.15–0.90, P<0.03), but not in women (2.09, 0.79–5.49, P=0.14);and (3) population clinical effects of A350A genotypes assessed in all 1756 subjects, showed that the case–control study findings reflected a protective HDL-C effect in men (CC: 1.17 mmol/L, CT: 1.22 mmol/L, and TT: 1.24 mmol/L, trend P=0.0062) and a deleterious LDL-C effect in women (CC: 3.58 mmol/L, CT: 3.72 mmol/L, and TT: 3.79 mmol/L, trend P=0.014). The allelic frequencies of the common SR-BI variants appear to be very similar in European and North American populations. The HDL-C effect increased with age. SR-BI A350A appears to have gender-specific and age-related effects on cholesterol transport lipoproteins.

Genome-wide scans reveal quantitative trait Loci on 8p and 13q related to insulin action and glucose metabolism: the San Antonio Family Heart Study.

Type 2 diabetes is a complex disease that arises from physiological disruptions of the body's sensitivity to insulin and ability to metabolize glucose. Multipoint linkage analyses for insulin sensitivity phenotypes were conducted in 1,280 Mexican Americans from 41 families who participated in the San Antonio Family Heart Study. A significant linkage signal (logarithm of odds [LOD] = 2.98) affecting corrected insulin response to glucose was detected on chromosome 13q between D13787 and D13S252, in the region where the MODY-4 gene has previously been mapped. Another signal on chromosome 13 was observed at D13S285 (LOD = 1.86), where the insulin receptor substrate 2 gene resides. Significant linkage (LOD = 3.09) for insulin response to glucose was found on chromosome 8 between D8S1130 and D8S1106, near the lipoprotein lipase and macrophage scavenger receptor genes. Multipoint analysis of abdominal skinfold with an LOD of 2.68 showed signals in the same region. There was also suggestive evidence for linkage of quantitative insulin sensitivity check index and fasting glucose to a previously reported location at D9S301 (LOD = 2.19). These results indicate that chromosomal locations on 8p and 13q might harbor genes that affect a variety of insulin- and glucose-related phenotypes that contribute to the observed variations in these important risk factors for diabetes in Mexican Americans.

Insights into cyclosporine A-induced atherosclerotic risk in transplant recipients: macrophage scavenger receptor regulation.

Clinical monitoring of organ-transplant recipients suggests that administration of cyclosporine (CsA) may increase the risk of atherosclerosis when compared with the general population. The purpose of this work is to demonstrate the utility of the in vitro Tamm-Horsfall protein (THP)-1 human monocyte cell culture model for determining drug-related atherosclerotic potential in macrophages. The effect of CsA on the mRNA expression of macrophage scavenger receptor genes including CD36, CD68, scavenger receptor (SR)-A, SR-BII, and lectin-like oxidized low-density lipoprotein receptor (LOX-1); the nuclear hormone receptors, including peroxisome-proliferator activated receptor (PPAR)gamma and liver-X-receptor (LXR)alpha; and the cholesterol efflux pump ABCA1 were investigated as markers of atherosclerotic progression. The THP-1 cells were cultured and differentiated into macrophages. The macrophages were then treated with CsA to assess gene expression. Time- (1, 2, 4, 8, and 24 hours) and dose- (concentrations [mg/L] corresponding to the trough [0.5], peak [1.25] and 4x peak [5]) dependency of CsA was assessed. The treated macrophage mRNA gene expression of CD36, CD68, and PPARgamma were up-regulated in the presence of CsA. Interestingly, SR-A, SR-BII, LOX-1, and LXRalpha expression appeared to be slightly down-regulated, and ABCA1 was relatively unchanged. Immunoblotting studies demonstrated that the protein expression of CD36 was unchanged or increased, PPARgamma was unchanged, and ABCA1 was unchanged or decreased at 4 and 8 hours. The results document CsA-induced mRNA and protein changes in receptors relevant to lipid-laden foam cell formation and demonstrate the utility of THP-1 macrophages for screening of atherosclerotic risk potential.