Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Accumulation of substantial numbers of monocyte/macrophages, as well as activated T lymphocytes, in focal areas of arterial intima appears to be a hallmark of atherogenesis. Our report demonstrated that lysophosphatidylcholine (lyso-PC), a polar phospholipid component that is increased in atherogenic lipoproteins, such as oxidized LDL and remnants lipoproteins in diabetic and type III hyperlipidemic patients, can upregulate adhesion molecules for monocytes and T lymphocytes, and growth factors, such as heparin-binding epidermal growth factor-like growth factor and PDGF-A and B chains. Recently we identified the novel receptor for oxidized LDL, named Lox-1. Therefore in this paper we summarize the importance of the interaction between oxidized LDL and its receptor, LOX-1 in terms of early stage of atherogenesis.
Diabetes Res Clin Pract 1999 Sep
PMID:Oxidized LDL and expression of monocyte adhesion molecules. 1058 64

Diabetes mellitus accelerating atherosclerosis was associated with the enhanced glycoxidative modification of lipoproteins. LOX-1, the endothelial oxidized LDL receptor might be involved in the pathogenesis of diabetic atherosclerosis. In this study, we examined the vascular expression of LOX-1 in streptozotocin-induced diabetic rats. We found that LOX-1 was significantly increased in diabetic rat aorta compared with nondiabetic control. Immunohistochemistry revealed that the most distinctive staining of LOX-1 was in the endothelial cells, especially in the bifurcations of artery branches from aorta. In cultured aortic endothelial cells, diabetic rat serum and advanced glycation endproducts-BSA induced LOX-1 expression, while control rat serum along with high glucose did not. Applying a competitive inhibition assay, we found that LOX-1 ligand activity was accumulated in the diabetic rat serum, mainly in VLDL/LDL fractions. In addition, VLDL/LDL prominently increased LOX-1 among all the lipoprotein fractions of diabetic rat serum. In conclusion, diabetes markedly upregulated LOX-1 expression in the aortic endothelial cells. The enhanced glycoxidative modification of lipoproteins may contribute to the underlying mechanisms.
 ...
PMID:Diabetes enhances lectin-like oxidized LDL receptor-1 (LOX-1) expression in the vascular endothelium: possible role of LOX-1 ligand and AGE. 1157 59

Recent progress in the study of atherosclerosis revealed that the proatherogenic property of LDL is attributable to oxidized LDL. Macrophages recruited to vascular wall phagocytose oxidized LDL and transformed into foam cells, which is a hallmark of atheroma. Endothelial cells also binds oxidized LDL and changes its phenotype to the status of "endothelial dysfunction." We successfully cloned the endothelial receptor for oxidized LDL, designated LOX-1. LOX-1-mediated action of oxidized LDL induces the decrease in NO release and the increased expression of adhesion molecules, which are typical changes in endothelial dysfunction. The expression of LOX-1 is quite inducible. Proinflammatory cytokines, etc. induce the expression of LOX-1 in vitro; and proatherogenic conditions, e.g., hypertension, hyperlipidemia, and diabetes, induce the expression of LOX-1 in vivo. This manner of expression suggests the importance of LOX-1 in pathological settings. LOX-1 binds not only oxidized LDL, but also binds apoptotic cells and activated platelets through the interaction with anionic phospholipids. This property might bridge atherosclerosis and thrombosis. A novel system to detect LOX-1 ligand in plasma detected the increased level of LOX-1 ligand in hypercholesterolemic rabbits compared with normal ones. This system might be useful to predict the status of endothelial function and the risk of ischemic heart disease.
 ...
PMID:[Molecular identification of LOX-1 and analysis of its pathophysiological role]. 1191 16

Oxidatively modified low-density lipoprotein (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, and it allows uptake of ox-LDL into endothelial cells. This receptor is transcriptionally upregulated by tumor necrosis factor-alpha, angiotensin II, shear stress and ox-LDL itself. The expression of this receptor activates a variety of intracellular processes that lead to expression of adhesion molecules and endothelial activation. This receptor is highly expressed in the blood vessels of animals and humans with hypertension, diabetes mellitus and atherosclerosis. Expression of this receptor may also be relevant in intra-arterial thrombogenesis and myocardial ischemia-reperfusion injury. Identification and regulation of this receptor and understanding of signal transduction pathways may lead to new therapies of diseases characterized by endothelial dysfunction.
 ...
PMID:Identification, regulation and function of a novel lectin-like oxidized low-density lipoprotein receptor. 1198 3

Lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1) was initially identified as the major receptor for oxidized LDL (OxLDL) in endothelial cells. Its inducible expression in macrophages and smooth muscle cell was also observed. LOX-1 is a Type II membrane protein with a typical C-type lectin structure at the extracellular C-terminus. It can be cleaved by an unknown protease at the extracellular juxtamembrane region to release the soluble form of LOX-1. The extracellular domains of LOX-1 are post-translationally modified by N-linked glycosylation. Mutagenesis studies revealed that the lectin domain of LOX-1 is the functional domain that recognizes the LOX-1 ligand. The C-terminal end residues and several conserved positively charged residues spanning the lectin domain are essential for OxLDL binding. LOX-1 activation by OxLDL causes endothelial changes that are characterized by activation of nuclear factor-kappaB through an increased reactive oxygen species, subsequent induction of adhesion molecules, and endothelial apoptosis. In vitro, expression of LOX-1 is induced by many inflammatory cytokines, oxidative stress, hemodynamic stimuli, and OxLDL. In vivo, the expression is enhanced in pro-atherogenic settings including, hypertension, hyperlipidemia, and diabetes, and, indeed, is accumulated in the atherosclerotic and glomerulosclerotic lesions. LOX-1 binds multiple classes of ligands that are implicated in the pathogenesis of atherosclerosis. Besides OxLDL, LOX-1 can recognize apoptotic/aged cells, activated platelets, and bacteria, implying versatile physiological functions. Taken together, all these findings support the possible contribution of LOX-1 to the pathogenesis of vascular disorders, particularly atherosclerosis. Development of antagonists for LOX-1 might be a good therapeutic approach to vascular diseases.
 ...
PMID:LOX-1, the receptor for oxidized low-density lipoprotein identified from endothelial cells: implications in endothelial dysfunction and atherosclerosis. 1216 30

Oxidized LDL and its receptors play important roles in atherosclerotic progression and atherosclerotic plaque rupture, by enlarging the lipid core and weakening the fibrous cap. Oxidized LDL, in fact, induces foam cell transformation of macrophages, production of matrix metalloproteinases(MMPs), and apoptosis of smooth muscle cells. Oxidized LDL concentrations in circulating blood in humans have been shown to be elevated in diabetes and atherosclerotic vascular diseases, especially acute coronary syndrome. Lectin-like oxidized LDL receptor-1(LOX-1) is a cell surface receptor for oxidized LDL, which is abundantly expressed in atherosclerotic plaques and is involved in oxidized LDL-induced MMP production and apoptosis. Soluble LOX-1 concentration in human blood also have been shown to be elevated in coronary heart diseases especially in acute coronary syndrome.
 ...
PMID:[Measurement of oxidized LDL and its soluble receptors]. 1520 53

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

The lesions of atherosclerosis represent a series of highly specific cellular and molecular responses. Low density lipoprotein (LDL), which may be modified by oxidation, glycation, aggregation, association with proteoglycans, or incorporation into immune complexes, is a major cause of injury to the endothelium and vascular smooth muscle cells (VSMC).The major major cell types involved in atherogenesis, macrophages and VSMC, are activated by pro-inflammatory stimuli including modified LDL. Modified LDL induces inflammatory responses in macrophages, migration and proliferation of SMC, and triggers foam cell formation. Scavenger receptors, including LOX-1, play a key role in foam cell formation by mediating the uptake of modified LDL. LOX-1 expression is detected in endothelial cells of early atherosclerosis lesions of human carotid arteries. Advanced lesions showed LOX-1 expression not only in endothelial cells but also in macrophages and more frequently in VSMC, and may be involved in foam cell transformation in macrophages and VSMC. The metabolic abnormalities that characterize diabetes, particularly hyperglycemia, free fatty acids, and insulin resistance, provoke molecular mechanisms that alter the function and structure of blood vessels. These include increased oxidative stress, intracellular signal transduction disturbances, and activation of the receptor for advanced glycation end products (R-AGE). Data showed that LOX-1 expression is enhanced by proatherogenic factors relevant to human diabetes, including high glucose, oxLDL, advance glycation end products, and C-reactive protein. LOX-1 expression increased also through oxygen species (ROS), endothelin-1 (ET-1), tumor necrosis factor-alpha (TNF-alpha), shear stress, activation of protein kinase-C (PKC), angiotensin-II (ANG-II), and through inflammatory pathways.
 ...
PMID:The expression and down stream effect of lectin like-oxidized low density lipoprotein 1 (LOX-1) in hyperglycemic state. 1793 9

LOX-1 is a multifunctional membrane receptor that binds and internalizes oxidized LDL (oxLDL). We tested the hypothesis that blockade of LOX-1 with an anti-LOX-1 antibody limits nephropathy in male rats with diabetes and dyslipidemia (ZS rats; F(1) hybrid product of Zucker fatty diabetic rats and spontaneous hypertensive heart failure rats). Lean ZS rats were controls, while untreated obese ZS (OM), ZS obese rats injected with nonspecific rabbit IgG (OM-IgG; 2 microg intravenous injection given weekly), and obese ZS rats given anti-LOX-1 rabbit antibody (OM-Ab; 2 microg intravenous injection given weekly) were the experimental groups. The rats were treated from 6 to 21 wk of age. All obese groups had severe dyslipidemia and hyperglycemia. Kidneys of obese rats expressed LOX-1 in capillaries and tubules, were larger, accumulated lipid, had intense oxidative stress, leukocyte infiltration, depressed mitochondrial enzyme level and function, and peritubular fibrosis (all P < 0.05 vs. lean ZS rats). Injections with LOX-1 antibody limited these abnormalities (P < 0.01 vs. data in OM or OM-lgG rats). In vitro, renal epithelial LOX-1 expression was verified in a cultured proximal tubule cell line. Our study indicates that anti-LOX-1 (vascular and epithelial) therapy may effectively reverse critical pathogenic elements of nephropathy in diabetes and dyslipidemia.
 ...
PMID:Anti-LOX-1 therapy in rats with diabetes and dyslipidemia: ablation of renal vascular and epithelial manifestations. 1798 13

The early nephropathy in obese, diabetic, dyslipidemic (ZS) rats is characterized by tubular lipid accumulation and pervasive inflammation, two critically interrelated events. We now tested the hypothesis that proximal tubules from ZS obese diabetic rats in vivo, and proximal tubule cells (NRK52E) exposed to oxidized LDL (oxLDL) in vitro, change their normally quiescent epithelial phenotype into a proinflammatory phenotype. Urine of obese diabetic rats contained more lipid peroxides, and LOX-1, a membrane receptor that internalizes oxidized lipids, was mobilized to luminal sites. Levels of ICAM-1 and focal adhesion kinase, which participate in leukocyte migration and epithelial dedifferentiation, respectively, were also upregulated in tubules. NRK52E cells exposed to oxLDL showed similar modifications, plus suppression of anti-inflammatory transcription factor peroxisome proliferator-activated receptor-delta. In addition, oxLDL impaired epithelial barrier function. These alterations were prevented by an anti-LOX-1 antibody. The data support the concept that tubular LOX-1 activation driven by lipid oxidants in the preurine fluid is critical in the inflammatory changes. We suggest that luminal lipid oxidants and abnormal tubular permeability may be partly responsible for the renal tubulointerstitial injury of obesity, diabetes, and dyslipidemia.
 ...
PMID:LOX-1 and inflammation: a new mechanism for renal injury in obesity and diabetes. 1832 20


1 2 3 Next >>