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

Our present knowledge on chemically modified proteins and their receptor systems is originated from a proposal by Goldstein and Brown in 1979 for the receptor for acetylated LDL which is involved in foam cell formation, one of critical steps in atherogenesis. Subsequent extensive studies using oxidized LDL (OxLDL) as a representative ligand disclosed at least 11 different scavenger receptors which are collectively categorized as "scavenger receptor family". Advanced glycation endproducts (AGE) and their receptor systems have been studied independently until recent findings that AGE-proteins are also recognized as active ligands by scavenger receptors including class A scavenger receptor (SR-A), class B scavenger receptors such as CD36 and SR-BI, type D scavenger receptor (LOX-1) and FEEL-1/FEEL-2. Three messages can be summarized from these experiments; (i) endocytic uptake of OxLDL and AGE-proteins by macrophages or macrophage-derived cells is mainly mediated by SR-A and CD36, which is an important step for foam cell formation in the early stage of atherosclerosis, (ii) selective uptake of cholesteryl esters of high density lipoprotein (HDL) mediated by SR-BI is inhibited by AGE-proteins, suggesting a potential pathological role of AGE in a HDL-mediated reverse cholesterol transport system, (iii) a novel scavenger receptor is involved in hepatic clearance of plasma OxLDL and AGE-proteins.
 ...
PMID:Scavenger receptors for oxidized and glycated proteins. 1466 Oct 91

Endothelial cell dysfunction (ECD) is emerging as a common denominator for diverse cardiovascular abnormalities associated with inhibition of endothelial nitric oxide (NO) synthase (eNOS). Elevated levels of asymmetric dimethylarginine (ADMA), a potent eNOS inhibitor, are common in renal failure and may contribute to ECD. Through DNA microarray screening of genes modulated in human umbilical vein endothelial cells (HUVEC) by N(G)-nitro-l-arginine methyl ester (l-NAME), we found a 1.8-fold increase in low-density lipoprotein receptor-1 (LOX-1) expression. LOX-1 is a major endothelial receptor for oxidized low-density lipoproteins (OxLDL) and is assumed to play a role in the initiation and progression of atherosclerosis. Here, we confirmed the upregulation of LOX-1 mRNA and protein level by quantitative RT-PCR and Western blot analysis. Increased expression of LOX-1 was associated with the accumulation of DiI-labeled OxLDL (DiI-OxLDL) in ADMA- and l-NAME-pretreated HUVEC. To evaluate the contribution of LOX-1 in ADMA-induced accumulation of OxLDL by HUVEC, we used the competitive receptor inhibitor, soluble LOX-1. Treatment of HUVEC with soluble LOX-1 was associated with an approximately two- to threefold inhibition of DiI-OxLDL uptake in l-NAME- or ADMA-treated HUVEC. In conclusion, ADMA- or l-NAME-induced NO deficiency leads to the increased expression of LOX-1 mRNA and protein in HUVEC, which in turn results in the accumulation of OxLDL. Competition with LOX-1-soluble extracellular domain reduces OxLDL accumulation. In summary, elevated ADMA levels, i.e., in patients with renal failure, may be responsible for endothelial accumulation of OxLDL via upregulated LOX-1 receptor, thus contributing to endothelial lipidosis and dysfunction.
 ...
PMID:Upregulation of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in endothelial cells by nitric oxide deficiency. 1501 Mar 59

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

Infections, such as by Chlamydophilia pneumoniae, cytomegalovirus, herpes simplex virus, and Helicobacter pylori, have been shown to be involved in atherogenesis. Herpes simplex virus I (HSV-1) could infect vascular endothelial cells, and it has been shown that, when endothelial cells were activated with oxidized LDL (oxLDL), a number of cellular events are occurred, leading to endothelial cell dysfunction. Since LOX-1 is a major receptor for oxLDL on endothelial cells and its expression was increased in atherosclerosis, we investigated whether HSV1 infection can lead to the increase expression of LOX-1 in endothelial cells. LOX-1 mRNA expression determined by RT-PCR and LOX-1 promoter activity measured by luciferase assay were increased in endothelial cells following HSV-1 infection. This suggests that one of the mechanisms by which HSV-1 is involved in atherogenesis maybe the enhanced uptake of oxLDL via the increased expression of LOX-1 in endothelial cells.
 ...
PMID:Herpes simplex virus 1 induced LOX-1 expression in an endothelial cell line, ECV 304. 1527 8

There is strong evidence for the role of oxidative stress in all stages of atherosclerosis. Oxidized low density lipoprotein (ox-LDL), a marker of oxidative stress, is present in the plasma as well as in the atherosclerotic arteries of patients with atherosclerosis. Ox-LDL leads to endothelial activation, dysfunction and injury. Recently, a novel lectin-like receptor for ox-LDL (LOX-1) has been identified, primarily in the endothelial cells, that allows uptake of ox-LDL into endothelial cells. This receptor is transcriptionally upregulated by tumour necrosis factor-a, angiotensin II, shear stress and ox-LDL. The expression of this receptor activates a variety of intracellular processes that leads to expression of adhesion molecules and endothelial activation. Recent studies show that LOX-1 activation leads to the expression of CD40/40 L in endothelial cells and upregulation of matrix metalloproteinases. This receptor is highly expressed in blood vessels of animals and humans with hypertension, diabetes mellitus and atherosclerosis. Co-localization of LOX-1 along with ox-LDL in the rupture-prone plaque suggests that this receptor may be involved in the precipitation of acute myocardial ischemia. Identification and regulation of this receptor and understanding of signal transduction pathways may lead to new therapies in disease states characterized by endothelial dysfunction.
 ...
PMID:The role of LOX-1, a novel lectin-like receptor for oxidized low density lipoprotein, in atherosclerosis. 1530 3

Atherosclerosis is a slowly evolutive age-linked disease of large arteries, characterized by a local lipid deposition associated with a chronic inflammatory response, leading potentially to acute plaque rupture, thrombosis and ischemic heart disease. Atherogenesis is a complex sequence of events associating first expression of adhesion molecules, recruitment of mononuclear cells to the endothelium, local activation of leukocytes and inflammation, lipid accumulation and foam cell formation. Low density lipoproteins (LDLs) become atherogenic after undergoing oxidation by vascular cells, that transform them into highly bioreactive oxidized LDL (oxidized LDLs). Oxidized LDLs are involved in foam cell formation, and trigger proatherogenic events such as overexpression of adhesion molecules, chemoattractant agents growth factors and cytokines involved in the inflammatory process, cell proliferation and apoptosis. Moreover, this toxic effect of oxidized LDLs plays probably a role in plaque erosion/rupture and subsequent atherothrombosis. Several biological effects of oxidized LDLs are mediated through changes in the activity of transcription factors and subsequently in gene expression. Oxidized LDLs exert a biphasic effect on the redox-sensitive transcription factor NF-kappaB, which can be activated thereby up-regulating proinflammatory gene expression, such as adhesion molecules, tissue factor, scavenger receptor LOX-1. On the other hand, higher concentrations of oxidized LDLs may inhibit NF-kappaB activation triggered by inflammatory agents such as LPS, and may thereby exert an immunosuppressive effect. This review is an attempt to clarify the mechanism by which oxidized LDLs may up- or down-regulate NF-kappaB, the role of NF-kappaB activation (or inhibition), and the consequences of the oxidized LDLs-mediated NF-kappaB dysregulation and their potential involvement in atherosclerosis.
 ...
PMID:Dual role of oxidized LDL on the NF-kappaB signaling pathway. 1534 45

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.
 ...
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

Vein grafts interposed to arteries are susceptible to the development of accelerated atherosclerosis. The role of lectinlike oxidized LDL (ox-LDL) receptor-1 (LOX-1) expression in the atherosclerotic lesions of vein grafts has not been clarified. The current study was designed to examine the expression of LOX-1 in vein grafts atherosclerosis and the modulating effect of losartan on it. Autologous external jugular veins were grafted to common carotid arteries in 30 male New Zealand White rabbits. After surgery, rabbits were fed with high cholesterol diet (HC), high cholesterol diet plus losartan (10 mg/kg/day, LHC) or regular chow (control, n = 10 in each group) for 12 weeks. LOX-1 expressions in the grafts were examined by immunohistochemistry, semi-quantitative RT-PCR and Western blot. Neointimal hyperplasia was observed in all vein grafts characterized by extensive intimal thickening. Atherosclerotic lesions were found in vein grafts of HC group, which were attenuated by losartan. Losartan also reduced the vein grafts atherosclerotic plaque vulnerability. LOX-1 expression was low in the endothelium and neointima of vein grafts in control group and was significantly increased in the endothelium and atherosclerotic lesions in HC group but not in LHC group. In conclusion, LOX-1 was expressed in endothelium and neointima of autologous vein grafts of rabbits. Increased LOX-1 expression was associated with vein grafts atherosclerosis development. Downregulation of LOX-1 by losartan might contribute to its attenuating effect on vein grafts atherosclerosis.
Atherosclerosis 2004 Dec
PMID:Upregulation of lectinlike oxidized low-density lipoprotein receptor-1 expression contributes to the vein graft atherosclerosis: modulation by losartan. 1553 Aug 98

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.
 ...
PMID:The lectin-like oxidized low-density lipoprotein receptor and its role in atherosclerosis. 1572 24

The endothelial lectinlike, oxidatively (ox-) modified LDL receptor LOX-1 is a critical player in the pathogenesis of atherosclerosis and myocardial ischemia. Ox-LDL binding of LOX-1 results in the expression of various adhesion molecules, which attract monocytes to endothelial cells, an initial step in atherogenesis. We wished to examine the role of the ox-LDL/LOX-1 signaling pathway in fibroblasts, which naturally express low levels of LOX-1. Rat cardiac fibroblasts were transfected with either cytomegalovirus (CMV)-LOX-1wt (amino acids [aa] 1 to 273) or CMV-LOX-1(1-261) (an ox-LDL-binding negative mutant, aa 1 to 261) plasmid. Western blots showed that LOX-1 protein expression was increased significantly in cells transfected with CMV-LOX-1wt or CMV-LOX-1(1-261) plasmid (P<0.01 vs control). Fibroblasts transfected with CMV-LOX-1wt showed ox-LDL binding, whereas fibroblasts without transfection and those transfected with CMV-LOX-1(1-261) did not bind ox-LDL. Compared with untransfected cells, ox-LDL treatment (50 microg/mL, 24 hours) markedly induced the expression of the leukocyte adhesion molecules intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM)-1 as well as matrix metalloproteinase (MMP)-1 in cells transfected with CMV-LOX-1wt (P<0.05) but not in cells transfected with CMV-LOX-1(1-261). Concurrently, ox-LDL treatment enhanced the phosphorylation of p38 mitogen-activated protein kinase (MAPK) (P<0.05 vs control) in CMV-LOX-1wt-transfected cells. These data suggest that in cardiac fibroblasts, ox-LDL binds to LOX-1 and activates p38 MAPK, followed by the expression of ICAM-1, VCAM-1, and MMP-1. Thus, fibroblasts transform into an endothelial phenotype on transfection with CMV-LOX-1wt and subsequent exposure to ox-LDL. This study provides a useful model system (plasmid-transfected fibroblasts) to study the molecular biology of LOX-1.
 ...
PMID:Adhesion molecule expression in fibroblasts: alteration in fibroblast biology after transfection with LOX-1 plasmids. 1611 44


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>