Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have reported the cDNA cloning of a modified low-density-lipoprotein (LDL) receptor, designated lectin-like oxidized LDL receptor-1 (LOX-1), which is postulated to be involved in endothelial dysfunction and the pathogenesis of atherosclerosis. Here, we determined the organization of the human LOX-1 gene, including the 5'-regulatory region. The 5'-regulatory region contained several potential cis-regulatory elements, such as GATA-2 binding element, c-ets-1 binding element, 12-O-tetradecanoylphorbol 13-acetate-responsive element and shear-stress-responsive elements, which may mediate the endothelium-specific and inducible expression of LOX-1. The major transcription-initiation site was found to be located 29 nucleotides downstream of the TATA box and 61 nucleotides upstream from the translation-initiation codon. The minor initiation site was found to be 5 bp downstream from the major site. Most of the promoter activity of the LOX-1 gene was ascribed to the region (-150 to -90) containing the GC and CAAT boxes. The coding sequence was divided into 6 exons by 5 introns. The first 3 exons corresponded to the different functional domains of the protein (cytoplasmic, transmembrane and neck domains), and the residual 3 exons encoded the carbohydrate-recognition domain similar to the case of other C-type lectin genes. The LOX-1 gene was a single-copy gene and assigned to the p12.3-p13.2 region of chromosome 12. Since the locus for a familial hypertension has been mapped to the overlapping region, LOX-1 might be the gene responsible for the hypertension.
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PMID:Structure and chromosomal assignment of the human lectin-like oxidized low-density-lipoprotein receptor-1 (LOX-1) gene. 1008 42

LOX-1 (lectin-like oxidized LDL receptor) is a newly identified cell surface receptor for oxidized LDL mainly expressed in endothelial cells. Recombinant soluble LOX-1(LOX-Fc) was generated by fusing the extracellular domain of LOX-1 with the Fc portion of IgG. A novel sandwich enzyme immunoassay specific for LOX-1 ligand is designed, using LOX-Fc and anti-apoB antibody. This immunoassay was used to determine LOX-1 ligand activity in normal and Watanabe heritable hyperlipidemic (WHHL) rabbit plasma. LOX-Fc was further applied for staining of atherosclerotic lesions of WHHL rabbits. LOX-1 ligand levels were significantly elevated in the plasma of hyperlipidemic rabbits compared with controls. Furthermore, LOX-1 ligand activity was detected in the atherosclerotic lesions in situ. These results support the potential roles of LOX-1 interacting with its ligand in the pathogenesis of atherosclerosis, which is enhanced in hyperlipidemia.
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PMID:Accumulation of LOX-1 ligand in plasma and atherosclerotic lesions of Watanabe heritable hyperlipidemic rabbits: identification by a novel enzyme immunoassay. 1126 89

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a major endothelial receptor for oxidized low-density lipoprotein, and is assumed to play a proatherogenic role in atherosclerosis. LOX-1 expression is induced by inflammatory cytokines as well as by proatherogenic stimuli. LOX-1 protein binds agedapoptotic cells, activated platelets, and bacteria, suggesting that it may have diverse activities in vivo. Here, we reveal a role for LOX-1 in endotoxin-induced inflammation. In a model of endotoxemia, injection of a high dose of endotoxin into rats induced leukopenia within 1 h and death of the animals within 24 h. Preadministration of anti-LOX-1 antibody reduced the degree of leukopenia and completely rescued the animals, whereas control IgG did not. In a model of low-dose endotoxin-induced uveitis, anti-LOX-1 antibody efficiently suppressed leukocyte infiltration and protein exudation. In situ videomicroscopic analyses of leukocyte interactions with retinal veins revealed that anti-LOX-1 antibody reduced the number of rolling leukocytes and increased the velocity of rolling, suggesting that LOX-1 functions as a vascular tethering ligand. The ability of LOX-1 to capture leukocytes under physiologic shear was confirmed in an in vitro flow model. Thus, LOX-1 is an adhesion molecule involved in leukocyte recruitment and may represent an attractive target for modulation of endotoxin-induced inflammation.
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PMID:Lectin-like oxidized LDL receptor-1 is a cell-adhesion molecule involved in endotoxin-induced inflammation. 1253 55

Endothelial dysfunction is associated with pathological vascular conditions including atherosclerosis, hypertension, and diabetes. The oxidatively modified form of low-density lipoprotein (LDL) is recognized as a major cause of endothelial dysfunction in atherogenesis. As the receptor for oxidized LDL in endothelial cells, we have identified the lectin-like oxidized LDL receptor-1 (LOX-1). LOX-1 is up-regulated by products of oxidative stresses and the molecules that induce oxidative stresses. Activation of LOX-1 induces the generation of reactive oxygen species and decreases NO released from endothelial cells. LOX-1 activation further induces the expression of endothelin-1, AT(1) receptor, and cell adhesion molecules. Together with these properties, LOX-1 works as an adhesion molecule for activated platelets and neutrophils. Thus, LOX-1, within the close relationships between oxidative stress generation and response, enhances functional changes in endothelial cells that are relevant to the disturbed vascular homeostasis under pathological settings.
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PMID:Stress and vascular responses: endothelial dysfunction via lectin-like oxidized low-density lipoprotein receptor-1: close relationships with oxidative stress. 1268 39

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.
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PMID:Insights into cyclosporine A-induced atherosclerotic risk in transplant recipients: macrophage scavenger receptor regulation. 1508 24

Lectin-like oxidized low-density lipoprotein receptor (LOX-1) and monocyte chemoattractant protein-1 (MCP-1) are molecules involving in the initiation and progression of atherosclerosis. In order to examine a possible difference in LOX-1 and MCP-1 expressions depending on the severity of early stage of atherosclerosis, we investigated atherosclerotic changes by exposure to hypertension and hyperlipidemia in common carotid arteries (CCAs) of stroke-prone spontaneously hypertensive rat (SHR-SP). Three rat model groups such as control [Wistar Kyoto rat (WKY) group], hypertension (SHR-SP group) and hypertension + hyperlipidemia [SHR-SP + high fat and cholesterol (HFC) group] were used. Body weights, brain weights, systolic blood pressures and serum levels of total cholesterol, low-density lipoprotein and triglyceride were measured at 0, 5, 10 and 15 days after appropriate diet. Immunohistochemistry showed that the positive area and the strength of LOX-1 and MCP-1 were larger in the SHR-SP + HFC group than in the SHR-SP group, while no immunoreactivities were found in the WKY group. Conventional RT-PCR and real-time PCR analyses showed that mRNAs of those in the SHR-SP group were higher with greater up-regulation in the SHR-SP + HFC group. LOX-1 and MCP-1 expressions were coordinately up-regulated at mRNA and protein levels in an early stage of sclerosis depending on the severity of atherosclerotic stress. Activations of LOX-1 and MCP-1 are collectively involved in the early stage of atherosclerosis.
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PMID:Severity dependent up-regulations of LOX-1 and MCP-1 in early sclerotic changes of common carotid arteries in spontaneously hypertensive rats. 1549 20

The pathogenesis of posttransplant coronary artery disease, which is thought to be a major form of chronic rejection after cardiac transplantation, is not fully understood. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) on endothelial cells induces reduction of NO release and up-regulation of adhesion molecules, thereby contributing to the development of vascular atherosclerosis. Herein, we investigated the expression of LOX-1 mRNA in murine allografted hearts that develop diffuse coronary obstruction. Allogeneic (C57BL/6 to BALB/c) and syngeneic (C57BL/6 to C57BL/6) heterotopic cardiac transplants were removed the 10th posttransplant day. LOX-1 mRNA expression was measured by RT-PCR. The heartbeat of the allografts gradually weakened and was almost stopped on day 10, whereas syngeneic hearts continued to pulsate throughout the experiment. Histologically, allografts showed fibrous luminal narrowing of the coronary arteries with severe mononuclear cell infiltration. In contrast, the vascular architecture of syngeneic grafts was almost normal. Marked increase in LOX-1 mRNA expression was observed only in allografts. The results indicate that alloimmune responses induce up-regulation of LOX-1 mRNA in transplanted hearts. Increased LOX-1 may be involved in the progression of obstructive vascular changes.
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PMID:Expression of lectin-like oxidized low-density lipoprotein receptor-1 in allografted hearts. 1556 Dec 73

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) may play an important role in atherosclerosis by inducing leukocyte adhesion molecules, such as intercellular and vascular cell adhesion molecule-1 (intercellular adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1]). We hypothesized that eplerenone, a novel selective aldosterone blocker, produces inhibition of LOX-1-mediated adhesion molecules, suppresses mitogen-activated protein (MAP) kinase and its downstream effector p90 ribosomal S6 kinase (p90RSK) through the protein kinase Cepsilon (PKCepsilon) pathway, and improves endothelial function by inhibition of Rho-kinase in the renal cortex of Dahl salt-sensitive hypertensive (DS) and salt-resistant (DR) rats. Eplerenone (10, 30, and 100 mg/kg per day) was given from the age of 6 weeks to the left ventricular hypertrophy stage (11 weeks) for 5 weeks. At 11 weeks, expression levels of LOX-1, ICAM-1, VCAM-1, and Rho-kinase were higher in DS rats than in DR rats and were decreased by eplerenone. Similarly, upregulated phosphorylation of PKCepsilon, MAP kinase, and p90RSK in DS rats was also inhibited by eplerenone. In contrast, downregulated endothelial nitric oxide synthase mRNA was increased by eplerenone to a similar degree as after treatment with Y-27632, a selective Rho-kinase inhibitor. Eplerenone administration resulted in significant improvement in glomerulosclerosis (eplerenone 10 mg, -61%; 30 mg, -78%; and 100 mg, -84% versus DS; P<0.01, respectively) and urinary protein (10 mg, -78%; 30 mg, -87%; and 100 mg, -88% versus DS; P<0.01, respectively). These results suggest that the renoprotective effects of eplerenone may be partly caused by inhibition of LOX-1-mediated adhesion molecules and PKCepsilon-MAP kinase-p90RSK pathway, and improvement in endothelial function.
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PMID:Eplerenone shows renoprotective effect by reducing LOX-1-mediated adhesion molecule, PKCepsilon-MAPK-p90RSK, and Rho-kinase pathway. 1571 Jul 85

The lectin-like oxidized low-density lipoprotein receptor (LOX-1), a recently identified receptor that plays a role in the uptake of oxidized low-density lipoproteins into endothelial cells, has a pivotal role in the pathogenesis of atherosclerosis. The ways this receptor takes part in atherosclerosis is through uptake of oxidized low-density lipoproteins into endothelial cells, smooth muscle cells, and macrophages; decreasing nitric oxide production; increasing inflammatory cell recruitment; and increasing smooth muscle cell proliferation. LOX-1 is inducible and regulated by multiple factors known to underlie atherogenesis. Further understanding of this receptor may lead to potential molecular targets for prevention and treatment of atherosclerosis.
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PMID:The lectin-like oxidized low-density lipoprotein receptor and its role in atherosclerosis. 1572 24

Endothelial dysfunction induced by oxidized low-density lipoprotein (OxLDL) has been implicated in the pathogenesis of atherosclerosis and vasculopathy. Increased expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), the receptor for OxLDL in endothelial cells, has been demonstrated in the atherosclerotic plaques from experimental atherosclerotic animal models and human clinical samples. In vitro, activation of LOX-1 alters the expression of several endothelial cell genes that are involved in endothelial dysfunction. To investigate the role of LOX-1 in terms of both endothelial dysfunction and resultant vascular changes, we generated mice overexpressing LOX-1 (LOXtg) in C57BL/6 and apolipoprotein E-null mice (apoEKO) backgrounds. We found that the expression of the transgene was prominent in coronary vessels and cardiomyocytes. The enhancement of OxLDL uptake in LOXtg mice was consistent with the expression level of LOX-1. Under hyperlipidemic conditions, both OxLDL and 8-hydroxy-2'-deoxyguanosine accumulated in the coronary arteries of LOXtg/apoEKO mice. The expression of ICAM-1 and VCAM-1, as well as the number of macrophages around blood vessels, were significantly increased in LOXtg/apoEKO mice compared with control littermates. There were no differences in either the hemodynamic profile or the plasma lipid profile between the 2 groups of animals. LOXtg/apoEKO mice displayed accelerated intramyocardial vasculopathy, and the atheroma-like lesion area was increased 10-fold in the LOXtg/apoEKO mice compared with nontransgenic littermates after 3-weeks on the high-fat diet. Thus, it is demonstrated that LOX-1 overexpression promotes inflammatory intramyocardial vasculopathy in a hyperlipidemic mouse model, and this effect is probably mediated through the endothelial dysfunction induced by overexpression of LOX-1.
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PMID:Overexpression of lectin-like oxidized low-density lipoprotein receptor-1 induces intramyocardial vasculopathy in apolipoprotein E-null mice. 1596 18


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