The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses.
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Amyloidosis↗
Biomedical subjects
D M Stern
Publications and source records attributed to D M Stern.
Receptor for advanced glycation end products, inflammation, and accelerated periodontal disease in diabetes: mechanisms and insights into therapeutic modalities.
In hyperglycemic states found in diabetics, a nonenzymatic glycation and oxidation of proteins and lipids occurs. As a result, advanced glycation end products (AGEs), particularly N epsilon-(carboxymethyl)lysine, accumulate in the plasma and tissues of diabetic subjects. This accumulation has been linked to the development of pathogenic complications of diabetes. Many of the effects of AGEs are receptor-dependent and involve a multi-ligand member of the immunoglobulin superfamily of cell surface molecules. The best characterized of these is the receptor for advanced glycation end products (RAGE), which is expressed by multiple cell types including endothelium and mononuclear phagocytes. Based on data from a variety of sources, including studies of RAGE-deficient mice, it appears that RAGE plays a central role in oral infection, exaggerated inflammatory host responses, and destruction of alveolar bone in diabetes. It is possible that antagonists of RAGE might have a valuable adjunctive therapeutic role for the management of periodontal disease found in diabetics.
Alveolar Bone Loss↗
Diabetes-associated sustained activation of the transcription factor nuclear factor-kappaB.
Activation of the transcription factor nuclear factor-kappaB (NF-kappaB) has been suggested to participate in chronic disorders, such as diabetes and its complications. In contrast to the short and transient activation of NF-kappaB in vitro, we observed a long-lasting sustained activation of NF-kappaB in the absence of decreased IkappaBalpha in mononuclear cells from patients with type 1 diabetes. This was associated with increased transcription of NF-kappaBp65. A comparable increase in NF-kappaBp65 antigen and mRNA was also observed in vascular endothelial cells of diabetic rats. As a mechanism, we propose that binding of ligands such as advanced glycosylation end products (AGEs), members of the S100 family, or amyloid-beta peptide (Abeta) to the transmembrane receptor for AGE (RAGE) results in protein synthesis-dependent sustained activation of NF-kappaB both in vitro and in vivo. Infusion of AGE-albumin into mice bearing a beta-globin reporter transgene under control of NF-kappaB also resulted in prolonged expression of the reporter transgene. In vitro studies showed that RAGE-expressing cells induced sustained translocation of NF-kappaB (p50/p65) from the cytoplasm into the nucleus for >1 week. Sustained NF-kappaB activation by ligands of RAGE was mediated by initial degradation of IkappaB proteins followed by new synthesis of NF-kappaBp65 mRNA and protein in the presence of newly synthesized IkappaBalpha and IkappaBbeta. These data demonstrate that ligands of RAGE can induce sustained activation of NF-kappaB as a result of increased levels of de novo synthesized NF-kappaBp65 overriding endogenous negative feedback mechanisms and thus might contribute to the persistent NF-kappaB activation observed in hyperglycemia and possibly other chronic diseases.
Adult↗
Tissue factor--a receptor involved in the control of cellular properties, including angiogenesis.
Tissue factor (TF), the major initiator of blood coagulation, serves as a regulator of angiogenesis, tumor growth and metastasis. In several models, TF expression mediates upregulation of the proangiogenic vasular endothelial growth factor (VEGF) that can directly act on endothelial cells to promote vessel formation. This occurs through ligand binding, activation of signaling cascades, signal transduction and alteration of growth factor expression and is mediated by both, coagulation-dependent and -independent pathways. Depending on the cell type and the biological settings, TF seems to affect cellular properties through (i) factor VIIa (FVIIa)-dependent proteolysis of factor Xa (FXa) and thrombin and subsequent activation of proteinase activated receptor (PAR) -1 and PAR-2, (ii) through direct FVIIa signaling and mitogen activated protein (MAP) kinase activation, that is conferred by a not yet identified receptor, (iii) through interaction of FVII(a) proteolytic activity and signaling of the cytoplasmic domain and (iv) through cytoplasmic signaling independent of ligand binding. The role of phosphorylation of the cytoplasmic domain and the pathways controlling phosphorylation of TF remain poorly understood.
Animals↗
Summary of the 6th EASD/JDRF Oxfrod Workshop held at Keble College, Oxford, August 4-6, 2001.
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Antigens, CD34↗
The biology of the receptor for advanced glycation end products and its ligands.
Receptor for advanced glycation end products (RAGE) is a multiligand member of the immunoglobulin superfamily of cell surface molecules whose repertoire of ligands includes advanced glycation end products (AGEs), amyloid fibrils, amphoterins and S100/calgranulins. The overlapping distribution of these ligands and cells overexpressing RAGE results in sustained receptor expression which is magnified via the apparent capacity of ligands to upregulate the receptor. We hypothesize that RAGE-ligand interaction is a propagation factor in a range of chronic disorders, based on the enhanced accumulation of the ligands in diseased tissues. For example, increased levels of AGEs in diabetes and renal insufficiency, amyloid fibrils in Alzheimer's disease brain, amphoterin in tumors and S100/calgranulins at sites of inflammation have been identified. The engagement of RAGE by its ligands can be considered the 'first hit' in a two-stage model, in which the second phase of cellular perturbation is mediated by superimposed accumulation of modified lipoproteins (in atherosclerosis), invading bacterial pathogens, ischemic stress and other factors. Taken together, these 'two hits' eventuate in a cellular response with a propensity towards tissue destruction rather than resolution of the offending pathogenic stimulus. Experimental data are cited regarding this hypothesis, though further studies will be required, especially with selective low molecular weight inhibitors of RAGE and RAGE knockout mice, to obtain additional proof in support of our concept.
Amyloidosis↗
Hyperinsulinemia and vascular dysfunction: the role of nuclear factor-kappaB, yet again.
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Arteriosclerosis↗
Recognition of structurally diverse substrates by type II 3-hydroxyacyl-CoA dehydrogenase (HADH II)/amyloid-beta binding alcohol dehydrogenase (ABAD).
Human type II hydroxyacyl-CoA dehydrogenase/amyloid-beta binding alcohol dehydrogenase (HADH II/ABAD) is an oxidoreductase whose salient features include broad substrate specificity, encompassing 3-hydroxyacyl-CoA derivatives, hydroxysteroids, alcohols and beta-hydroxybutyrate, and the capacity to bind amyloid-beta peptide, leading to propagation of amyloid-induced cell stress. In this study, we examine the structure and enzymatic activity of the homologous rat HADH II/ABAD enzyme. We report the crystal structure of rat HADH II/ABAD as a binary complex with its NADH cofactor to 2.0 A resolution, as a ternary complex with NAD(+) and 3-ketobutyrate (acetoacetate) to 1.4 A resolution, and as a ternary complex with NADH and 17 beta-estradiol to 1.7 A resolution. This first crystal structure of an HADH II confirms these enzymes are closely related to the short-chain hydroxysteroid dehydrogenases and differ substantially from the classic, type I 3-hydroxyacyl-CoA dehydrogenases. Binding of the ketobutyrate substrate is accompanied by closure of the active site specificity loop, whereas the steroid substrate does not appear to require closure for binding. Despite the different chemical nature of the two bound substrates, the presentation of chemical groups within the active site of each complex is remarkably similar, allowing a general mechanism for catalytic activity to be proposed. There is a characteristic extension to the active site that is likely to accommodate the CoA moiety of 3-hydroxyacyl-CoA substrates. Rat HADH II/ABAD also binds amyloid-beta (1-40) peptide with a K(D) of 21 nM, which is similar to the interaction exhibited between this peptide and human HADH II/ABAD. These studies provide the first structural insights into HADH II/ABAD interaction with its substrates, and indicate the relevance of the rodent enzyme and associated rodent models for analysis of HADH II/ABAD's physiologic and pathophysiologic properties.
3-Hydroxyacyl CoA Dehydrogenases↗
Amyloid beta -peptide-binding alcohol dehydrogenase is a component of the cellular response to nutritional stress.
Amyloid beta-peptide-binding alcohol dehydrogenase (ABAD) is a member of the family of short chain dehydrogenase/reductases whose distinctive properties include the capacity to bind amyloid beta-peptide and enzymatic activity toward a broad array of substrates including n-isopropanol and beta-estradiol. In view of the wide substrate specificity of ABAD and its high activity on l-beta-hydroxyacyl-CoA derivatives, we asked whether it might also catalyze the oxidation of the ketone body d-3-hydroxybutyrate. This was indeed the case, and oxidation proceeded with K(m) of approximately 4.5 mm and V(max) of approximately 4 nmol/min/mg protein. When placed in medium with d-beta-hydroxybutyrate as the principal energy substrate, COS cells stably transfected to overexpress wild-type ABAD (COS/wtABAD) better maintained 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide reduction, cellular energy charge, and morphologic phenotype compared with COS/vector cells. Using a severe model of metabolic perturbation, transgenic mice with targeted neuronal expression of ABAD subjected to transient middle cerebral artery occlusion showed strokes of smaller volume and lower neurologic deficit scores in parallel with increased brain ATP and decreased lactate, compared with nontransgenic controls. These data suggest that ABAD contributes to the protective response to metabolic stress, especially in the setting of ischemia.
3-Hydroxybutyric Acid↗
Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases.
The receptor for advanced glycation end products (RAGE), a multi-ligand member of the immunoglobulin superfamily of cell surface molecules, interacts with distinct molecules implicated in homeostasis, development and inflammation, and certain diseases such as diabetes and Alzheimer's disease. Engagement of RAGE by a ligand triggers activation of key cell signalling pathways, such as p21ras, MAP kinases, NF-kappaB and cdc42/rac, thereby reprogramming cellular properties. RAGE is a central cell surface receptor for amphoterin, a polypeptide linked to outgrowth of cultured cortical neurons derived from developing brain. Indeed, the co-localization of RAGE and amphoterin at the leading edge of advancing neurites indicated their potential contribution to cellular migration, and in pathologies such as tumour invasion. Here we demonstrate that blockade of RAGE-amphoterin decreased growth and metastases of both implanted tumours and tumours developing spontaneously in susceptible mice. Inhibition of the RAGE-amphoterin interaction suppressed activation of p44/p42, p38 and SAP/JNK MAP kinases; molecular effector mechanisms importantly linked to tumour proliferation, invasion and expression of matrix metalloproteinases.
Animals↗
Expression of Egr-1 in late stage emphysema.
The transcription factor early growth response (Egr)-1 is an immediate-early gene product rapidly and transiently expressed after acute tissue injury. In contrast, in this report we demonstrate that lung tissue from patients undergoing lung reduction surgery for advanced emphysema, without clinical or anatomical evidence of acute infection, displays a selective and apparently sustained increase in Egr-1 transcripts and antigen, compared with a broad survey of other genes, including the transcription factor Sp1, whose levels were not significantly altered. Enhanced Egr-1 expression was especially evident in smooth muscle cells of bronchial and vascular walls, in alveolar macrophages, and some vascular endothelium. Gel shift analysis with (32)P-labeled Egr probe showed a band with nuclear extracts from emphysematous lung which was supershifted with antibody to Egr-1. Egr-1 has the capacity to regulate genes relevant to the pathophysiology of emphysema, namely those related to extracellular matrix formation and remodeling, thrombogenesis, and those encoding cytokines/chemokines and growth factors. Thus, we propose that further analysis of Egr-1, which appears to be up-regulated in a sustained fashion in patients with late stage emphysema, may provide insights into the pathogenesis of this destructive pulmonary disease, as well as a new facet in the biology of Egr-1.
Aged↗
RAGE: a new target for the prevention and treatment of the vascular and inflammatory complications of diabetes.
Although the underlying causes of hyperglycemia are multiple, a common thread associated with high levels of blood sugar is the development of a range of vascular and inflammatory complications that might seriously limit the quality and duration of life in affected individuals. Despite multiple aggressive efforts to prevent complications, diabetes remains the leading disease consuming healthcare dollars in the USA. This review focuses on the role of advanced glycation endproducts (AGEs) and their interaction with their signal-transduction AGE receptor (RAGE), in vascular and inflammatory cell perturbation and the chronic activation that underlies diabetes. Our studies provide mechanistic insights into complications within the macrovasculature and those ensuing from an exaggerated host response to invading bacteria, and suggest that blockade of RAGE might provide a potent and safe strategy for the prevention of complications that typify long-term diabetes.
Animals↗
Egr-1, a master switch coordinating upregulation of divergent gene families underlying ischemic stress.
Activation of the zinc-finger transcription factor early growth response (Egr)-1, initially linked to developmental processes, is shown here to function as a master switch activated by ischemia to trigger expression of pivotal regulators of inflammation, coagulation and vascular hyperpermeability. Chemokine, adhesion receptor, procoagulant and permeability-related genes are coordinately upregulated by rapid ischemia-mediated activation of Egr-1. Deletion of the gene encoding Egr-1 strikingly diminished expression of these mediators of vascular injury in a murine model of lung ischemia/reperfusion, and enhanced animal survival and organ function. Rapid activation of Egr-1 in response to oxygen deprivation primes the vasculature for dysfunction manifest during reperfusion. These studies define a central and unifying role for Egr-1 activation in the pathogenesis of ischemic tissue damage.
Animals↗
alpha-galactosyl epitopes on glycoproteins of porcine renal extracellular matrix.
BACKGROUND: The pig is the donor animal of choice for human xenotransplantation. In the most relevant pig-to-baboon model, pig organs transplanted into baboons are hyperacutely rejected by natural xenoantibodies, which mainly bind to alpha-galactosyl (alphaGal) epitopes expressed at the surface of endothelial cells. Recent advances in controlling hyperacute rejection have led to improved survival of these xenografts, and it is now important to identify alphaGal binding sites in other cells and tissues that may be subject to immunologic attack. To this end, we have studied whether alphaGal antibodies bind to glycated proteins of the extracellular matrix in the kidney and other organs most likely to be used for human xenotransplantation. METHODS: High-titer anti-alphaGal antibodies, similar to human natural xenoantibodies, were prepared in baboons, and their reactivity with components of pig extracellular matrix was tested by serology and immunohistology. RESULTS: The antibodies recognized epitopes of immobilized murine, bovine or porcine thyroglobulin, laminin, heparan sulfate proteoglycans, and fibronectin. In sections of pig tissue, the antibodies bound to endothelial and certain epithelial cells, as shown in previous studies, and also to mesenchymal cells, basement membranes, and extracellular matrices, in which they colocalized with matrix glycoproteins, especially laminin and heparan sulfate proteoglycans. CONCLUSIONS: These results suggest that when pig xenografts can be made to survive for prolonged periods, the reactivity of alphaGal antibody with matrix molecules can induce basement membrane and matrix lesions similar to those induced in laboratory animals by antilaminin and antiheparan sulfate proteoglycans antibodies.
Animals↗
A pathway leading to hypoxia-induced vascular fibrin deposition.
Hypoxemia has long been associated with vascular fibrin formation leading to thrombosis. This review describes a pathway through which mononuclear phagocytes and vascular smooth muscle cells upregulate tissue factor under hypoxic conditions. Increased expression of tissue factor triggers events leading to vascular fibrin deposition, providing insight into a novel mechanism potentially underlying thrombosis in ischemic vasculature.
Animals↗
RAGE: a multiligand receptor contributing to the cellular response in diabetic vasculopathy and inflammation.
RAGE is a multiligand member of the immunoglobulin superfamily of cell surface molecules whose properties extend the paradigm of ligand-receptor interactions. The receptor recognizes families of ligands with diverse structural features, such as advanced glycation endproducts (AGEs), amyloidogenic peptides/polypeptides, amphoterins, and S100/calgranulins rather than individual species. Engagement of RAGE by its ligands upregulates the receptor and initiates a cycle of sustained cellular perturbation; increased levels of RAGE on the cell surface make it an ideal target for subsequent ligand interactions and for propagating cellular dysfunction. At this time, the only means known to break this apparently vicious cycle appears to be blocking access to RAGE or removing the ligands. Taken together, these data suggest that RAGE has the potential to function as a progression factor in a range of disorders (AGEs are relevant to diabetes and other settings of oxidant stress, amyloidogenic peptides are relevant to amyloidoses, S100/calgranulins are relevant to inflammatory disorders, etc.) in which its ligands accumulate. The chronic juxtaposition of ligand and receptor triggers sustained cellular perturbation favoring mechanisms eventuating in tissue injury rather than those that would restore homeostasis.
Animals↗
Pulmonary expression of early growth response-1: biphasic time course and effect of oxygen concentration.
Hypoxia induces complex adaptive responses. In this report, induction of early growth response-1 (Egr-1) transcripts in lungs of mice subjected to hypoxia is shown to be dose and time dependent. Within 30 min of hypoxia, Egr-1 transcripts were approximately 20-fold elevated in 6% oxygen, approximately 5.2-fold increased by 10% oxygen, and returned to the normoxic baseline by 12% oxygen. Time course studies up to 48 h showed a biphasic profile with an initial steep rise in Egr-1 transcripts after 0.5 h of hypoxia and a second elevation beginning after 20-24 h. Hypoxic induction of Egr-1 was paralleled by enhanced expression of the downstream target gene tissue factor. Egr-1 and tissue factor antigen were visualized in bronchial and vascular smooth muscle and in alveolar macrophages. Egr-1 has the capacity to modulate expression of genes involved in the remodeling of the extracellular matrix and properties of smooth muscle, thus possibly contributing to the pulmonary response to chronic hypoxia.
Animals↗
Blockade of RAGE suppresses periodontitis-associated bone loss in diabetic mice.
Diabetes is associated with increased prevalence, severity, and progression of periodontal disease. To test the hypothesis that activation of RAGE (Receptor for Advanced Glycation End products) contributes to the pathogenesis of diabetes-associated periodontitis, we treated diabetic mice, infected with the human periodontal pathogen Porphyromonas gingivalis, with soluble RAGE (sRAGE). sRAGE is the extracellular domain of the receptor, which binds ligand and blocks interaction with, and activation of, cell-surface RAGE. Blockade of RAGE diminished alveolar bone loss in a dose-dependent manner. Moreover, we noted decreased generation of the proinflammatory cytokines TNF-alpha and IL-6 in gingival tissue, as well as decreased levels of matrix metalloproteinases. Gingival AGEs were also reduced in mice treated with sRAGE, paralleling the observed suppression in alveolar bone loss. These findings link RAGE and exaggerated inflammatory responses to the pathogenesis of destructive periodontal disease in diabetes.
Alveolar Bone Loss↗