-
[show abstract]
[hide abstract]
ABSTRACT: Myocardial infarction, stroke, and venous thromboembolism are characterized by oxygen deprivation. In hypoxia, biological responses are activated that evoke tissue damage. Rapid activation of early growth response-1 in hypoxia upregulates fundamental inflammatory and prothrombotic stress genes. We probed the mechanisms mediating regulation of early growth response-1 and demonstrate that hypoxia stimulates brisk generation of advanced glycation end products (AGEs) by endothelial cells. Via AGE interaction with their chief signaling receptor, RAGE, membrane translocation of protein kinase C-betaII occurs, provoking phosphorylation of c-Jun NH(2)-terminal kinase and increased transcription of early growth response-1 and its downstream target genes. These findings identify RAGE as a master regulator of tissue stress elicited by hypoxia and highlight this receptor as a central therapeutic target to suppress the tissue injury-provoking effects of oxygen deprivation.
Circulation Research 05/2008; 102(8):905-13. · 9.49 Impact Factor
-
Martin Andrassy,
John Igwe,
Frank Autschbach,
Christian Volz,
Andrew Remppis,
Markus F Neurath,
Erwin Schleicher,
Per M Humpert, Thoralf Wendt,
Birgit Liliensiek, [......],
Stephan Schiekofer,
Kirsten Thiele,
Jiang Chen,
Rose Kientsch-Engel,
Ann-Marie Schmidt,
Wolfgang Stremmel,
David M Stern,
Hugo A Katus,
Peter P Nawroth,
Angelika Bierhaus
[show abstract]
[hide abstract]
ABSTRACT: Oxidative and carbonyl stress leads to generation of N(epsilon)-carboxymethyllysine-modified proteins (CML-mps), which are known to bind the receptor for advanced glycation end products (RAGE) and induce nuclear factor (NF)-kappaB-dependent proinflammatory gene expression. To determine the impact of CML-mps in vivo, RAGE-dependent sustained NF-kappaB activation was studied in resection gut specimens from patients with inflammatory bowel disease. Inflamed gut biopsy tissue demonstrated a significant up-regulation of RAGE and increased NF-kappaB activation. Protein extracts from the inflamed zones, but not from noninflamed resection borders, caused perpetuated NF-kappaB activation in cultured endothelial cells, which was mediated by CML-mps including CML-modified S100 proteins. The resulting NF-kappaB activation, lasting 5 days, was primarily inhibited by either depletion of CML-mps or by the addition of sRAGE, p44/42 and p38 MAPKinase-specific inhibitors. Consistently, CML-mps isolated from inflamed gut areas and rectally applied into mice caused NF-kappaB activation, increased proinflammatory gene expression, and histologically detectable inflammation in wild-type mice, but not in RAGE-/- mice. A comparable up-regulation of NF-kappaB and inflammation on rectal application of CML-mps was observed in IL-10-/- mice. Thus, CML-mps generated in inflammatory lesions have the capacity to elicit a RAGE-dependent intestinal inflammatory response.
American Journal Of Pathology 11/2006; 169(4):1223-37. · 4.89 Impact Factor
-
Diabetes Care 06/2006; 29(5):1111-3. · 8.09 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Previous studies demonstrated that induction of diabetes with streptozotocin (stz) accelerated atherosclerosis in hyperlipidemic apo E null (-/-) mice. Blockade of the Receptor for Advanced Glycation Endproducts (RAGE) in those animals suppressed acceleration of atherosclerotic lesion area, in a manner independent of changes in levels of glucose, insulin or lipids. In the present studies, we extended these concepts to a murine model of type 2 diabetes, and bred apo E -/- mice into the db/db background. Db/db mice are a model of obesity and insulin resistance-mediated hyperglycemia. Compared to apo E -/- m/db (non-diabetic) mice, apo E -/- db/db (diabetic) mice displayed accelerated atherosclerosis at the aortic sinus. Consistent with an important role for RAGE in this process, administration of soluble (s) RAGE, the extracellular ligand-binding domain of RAGE, resulted in significantly reduced atherosclerotic lesion area in a glycemia- and lipid-independent manner. In parallel, apo E -/- db/db mice displayed RAGE-dependent enhanced expression of Vascular Cell Adhesion Molecule-1, tissue factor and matrix metalloproteinase (MMP)-9 antigen/activity in aortae compared to non-diabetic animals. In addition, consistent with the premise that upregulation of RAGE ligands and RAGE occurs even in the non-diabetic, hyperlipidemic state, albeit to lesser degrees than in diabetes, administration of sRAGE to apo E -/- m/db mice resulted in decreased atherosclerotic lesion area at the aortic sinus. Taken together, these findings establish a new murine model for the study of atherosclerosis in type 2 diabetes and highlight important roles for RAGE in proatherogenic mechanisms in hyperglycemia triggered by insulin resistance.
Atherosclerosis 04/2006; 185(1):70-7. · 3.79 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Advanced glycation end products (AGEs), S100/calgranulins, HMGB1-proteins, amyloid-beta peptides, and the family of beta-sheet fibrils have been shown to contribute to a number of chronic diseases such as diabetes, amyloidoses, inflammatory conditions, and tumors by promoting cellular dysfunction via binding to cellular surface receptors. The receptor for AGEs (RAGE) is a multiligand receptor of the immunoglobulin superfamily of cell surface molecules acting as counter-receptor for these diverse molecules. Engagement of RAGE converts a brief pulse of cellular activation to sustained cellular dysfunction and tissue destruction. The involvement of RAGE in pathophysiologic processes has been demonstrated in murine models of chronic disease using either a receptor decoy such as soluble RAGE (sRAGE), RAGE neutralizing antibodies, or a dominant-negative form of the receptor. Studies with RAGE-/- mice confirmed that RAGE contributes, at least in part, to the development of late diabetic complications, such as neuropathy and nephropathy, macrovascular disease, and chronic inflammation. Furthermore, deletion of RAGE provided protection from the lethal effects of septic shock caused by cecal ligation and puncture (CLP). In contrast, deletion of RAGE had no effect on the host response in delayed-type hypersensitivity (DTH). Despite the lack of effect seen in adaptive immunity by the deletion of RAGE, administration of the receptor decoy, sRAGE, still afforded a protective effect in RAGE-/- mice. Thus, sRAGE is likely to sequester ligands, thereby preventing their interaction with other receptors in addition to RAGE. These data suggest that, just as RAGE is a multiligand receptor, its ligands are also likely to recognize several receptors in mediating their biologic effects.
Journal of Molecular Medicine 12/2005; 83(11):876-86. · 4.67 Impact Factor
-
Gaetano R Barile,
Sophia I Pachydaki,
Samir R Tari,
Song E Lee,
Christine M Donmoyer,
Wanchao Ma,
Ling Ling Rong,
Loredana G Buciarelli, Thoralf Wendt,
Heidi Hörig,
Barry I Hudson,
Wu Qu,
Alan D Weinberg,
Shi Fang Yan,
Ann Marie Schmidt
[show abstract]
[hide abstract]
ABSTRACT: The receptor for advanced glycation end products (AGEs) has been implicated in the pathogenesis of diabetic complications. This study was conducted to characterize the role of the RAGE axis in a murine model of nonproliferative diabetic retinopathy (NPDR).
The retinas of hyperglycemic, hyperlipidemic (HGHL, apolipoprotein E(-/-) db/db) mice were examined for the development of early retinal vascular lesions of NPDR and compared to littermates at 6 months of age. Neural function was assessed with electroretinography. Immunohistochemistry, real-time RT-PCR, autofluorescence, and ELISA studies were used to localize and quantify the AGE/RAGE axis. Soluble RAGE, a competitor of cellular RAGE for its ligands, was administered to assess the impact of RAGE blockade.
Early inner retinal neuronal dysfunction, manifested by prolonged latencies of the oscillatory potentials and b-wave, was detected in hyperglycemic mice. HGHL mice exhibited accelerated development of acellular capillaries and pericyte ghosts compared with littermate control animals. AGEs were localized primarily to the vitreous cavity and internal limiting membrane (ILM) of the retina, where they were intimately associated with the footplates of RAGE-expressing Müller cells. AGE accumulation measured by ELISA was increased within the retinal extracellular matrix of hyperglycemic mice. AGE fluorescence and upregulation of RAGE transcripts was highest in the retinas of HGHL mice, and attenuation of the RAGE axis with soluble RAGE ameliorated neuronal dysfunction and reduced the development of capillary lesions in these mice.
In early diabetic retinopathy, the RAGE axis, comprising the cellular receptor and its AGE ligands, is amplified within the retina and is accentuated along the vitreoretinal interface. Antagonism of the RAGE axis in NPDR reduces neurovascular perturbations, providing an important therapeutic target for intervention.
Investigative Ophthalmology & Visual Science 09/2005; 46(8):2916-24. · 3.60 Impact Factor
-
Per M Humpert,
Renate Neuwirth,
Marco J Battista,
Olga Voronko,
Maximilian von Eynatten,
Ilze Konrade,
Gottfried Rudofsky, Thoralf Wendt,
Andreas Hamann,
Michael Morcos,
Peter P Nawroth,
Angelika Bierhaus
Diabetes Care 05/2005; 28(4):934-6. · 8.09 Impact Factor
-
Ling Ling Rong,
Shi-Fang Yan, Thoralf Wendt,
Diana Hans,
Sophia Pachydaki,
Loredana G Bucciarelli,
Adebukola Adebayo,
Wu Qu,
Yan Lu,
Konstantin Kostov,
Evanthia Lalla,
Shi Du Yan,
Clifton Gooch,
Matthias Szabolcs,
Werner Trojaborg,
Arthur P Hays,
Ann Marie Schmidt
[show abstract]
[hide abstract]
ABSTRACT: Axotomy of peripheral nerve stimulates events in multiple cell types that initiate a limited inflammatory response to axonal degeneration and simultaneous outgrowth of neurites into the distal segments after injury. We found that pharmacological blockade of RAGE impaired peripheral nerve regeneration in mice subjected to RAGE blockade and acute crush of the sciatic nerve. As our studies revealed that RAGE was expressed in axons and in infiltrating mononuclear phagocytes upon injury, we tested the role of RAGE in these distinct cell types on nerve regeneration. Transgenic mice expressing signal transduction-deficient RAGE in mononuclear phagocytes or peripheral neurons were generated and subjected to unilateral crush injury to the sciatic nerve. Transgenic mice displayed decreased functional and morphological recovery compared with littermate controls, as assessed by motor and sensory conduction velocities; and myelinated fiber density. In double transgenic mice expressing signal transduction deficient RAGE in both mononuclear phagocytes and peripheral neurons, regeneration was even further impaired, suggesting the critical interplay between RAGE-modulated inflammation and neurite outgrowth in nerve repair. These findings suggest that RAGE signaling in inflammatory cells and peripheral neurons plays an important role in plasticity of the peripheral nervous system.
The FASEB Journal 01/2005; 18(15):1818-25. · 5.71 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Receptor for AGE (RAGE) is a multi-ligand member of the immunoglobulin superfamily of cell surface molecules. Engagement of RAGE by its signal transduction ligands evokes inflammatory cell infiltration and activation in the vessel wall. In diabetes, when fueled by oxidant stress, hyperglycemia, and superimposed stresses such as hyperlipidemia or acute balloon/endothelial denuding arterial injury, the ligand-RAGE axis amplifies vascular stress and accelerates atherosclerosis and neointimal expansion. In this brief synopsis, we review the use of rodent models to test these concepts. Taken together, our findings support the premise that RAGE is an amplification step in vascular inflammation and acceleration of atherosclerosis. Future studies must rigorously test the potential impact of RAGE blockade in human subjects; such trials are on the horizon.
Arteriosclerosis Thrombosis and Vascular Biology 09/2004; 24(8):1342-9. · 6.37 Impact Factor
-
Berend Isermann,
Angelika Bierhaus,
Per M Humpert,
Gottfried Rudofsky,
Triantafyllos Chavakis,
Robert Ritzel, Thoralf Wendt,
Michael Morcos,
Christian Kasperk,
Andreas Hamann,
Peter P Nawroth
[show abstract]
[hide abstract]
ABSTRACT: Acausal relation between hyperglycemia and accelerated atherosclerosis has been recently suggested. The AGE-RAGE interaction is a potential mechanism underlying the accelerated atherosclerosis. Hyperglycemia causes via nonenzymatic glycation the formation of AGEs (advanced glycation endproducts). AGEs as well as other ligands like S100/Calgranulin and Amphoterin mediate receptor-independent and -dependent (via the interaction with RAGE) effects. The ligand-RAGE-interaction results in an activation of NF-kappaB, increased expression of cytokines, chemokines, and adhesion molecules and induces oxidative stress. A relevant role of the ligand-RAGE-interaction has been demonstrated in in vivo studies, both for the accelerated atherosclerosis and increased neointima formation in diabetes mellitus. Recent data analysing atherosclerotic lesions of diabetic patients provide further evidence for the pathogenetic role of the RAGE-ligand-interaction. In addition, new experimental data established that AGEs interact with other receptors than RAGE, while RAGE interacts with a diverse group of ligands. Thus, further studies are needed for the characterization of the ligand-RAGE-interaction. These studies will provide a rationale for the development of new therapeutic approaches for accelerated atherosclerosis in diabetes mellitus.
Herz 09/2004; 29(5):504-9. · 0.92 Impact Factor
-
Berend Isermann,
Angelika Bierhaus,
Per M. Humpert,
Gottfried Rudofsky,
Triantafyllos Chavakis,
Robert Ritzel, Thoralf Wendt,
Michael Morcos,
Christian Kasperk,
Andreas Hamann,
Peter P. Nawroth
[show abstract]
[hide abstract]
ABSTRACT: Krzlich konnte ein Zusammenhang zwischen der Hyperglykmie und der akzelerierten Atherosklerose im Rahmen des Diabetes mellitus hergestellt werden. Einen mglichen pathogenetischen Mechanismus der akzelerierten Atherosklerose stellt die AGE-RAGE-Interaktion dar. Die Hyperglykmie fhrt durch nichtenzymatische Glykierung zur Entstehung von AGEs (advanced glycation endproducts). AGEs, aber auch andere Liganden wie S100/Calgranulin und Amphoterin, vermitteln rezeptorunabhngige und rezeptorabhngige (z.B. via RAGE-Interaktion) Effekte. Die RAGE-Liganden-Interaktion fhrt zu einer vermehrten Aktivierung von NF-B, eine vermehrte Expression von Zytokinen, Chemokinen und Adhsionsmoleklen und induziert oxidativen Stress. Tierexperimentelle Daten belegen die Relevanz der Liganden-RAGE-Interaktion fr die akzelerierte Atherosklerose und die vermehrte Neointimabildung im Rahmen eines Diabetes mellitus. Erste Analysen atherosklerotischer Lsionen von Diabetikern untersttzen ebenfalls eine pathogenetische Rolle der Liganden-RAGE-Interaktion fr die Atherosklerose. Neue experimentelle Daten belegen, dass auf der einen Seite AGEs mit weiteren Rezeptoren (auer RAGE), auf der anderen Seite RAGE mit diversen Liganden interagiert. Weitere Untersuchungen zur Charakterisierung der Liganden-RAGE-Interaktion werden das erforderliche Grundlagenwissen zur Entwicklung innovativer Therapieanstze der akzelerierten Atherosklerose beim Diabetes mellitus bereitstellen.A causal relation between hyperglycemia and accelerated atherosclerosis has been recently suggested. The AGE-RAGE interaction is a potential mechanism underlying the accelerated atherosclerosis. Hyperglycemia causes via nonenzymatic glycation the formation of AGEs (advanced glycation endproducts). AGEs as well as other ligands like S100/Calgranulin and Amphoterin mediate receptor-independent and -dependent (via the interaction with RAGE) effects. The ligand-RAGE-interaction results in an activation of NF-B, increased expression of cytokines, chemokines, and adhesion molecules and induces oxidative stress. A relevant role of the ligand-RAGE-interaction has been demonstrated in in vivo studies, both for the accelerated atherosclerosis and increased neointima formation in diabetes mellitus. Recent data analysing atherosclerotic lesions of diabetic patients provide further evidence for the pathogenetic role of the RAGE-ligand-interaction. In addition, new experimental data established that AGEs interact with other receptors than RAGE, while RAGE interacts with a diverse group of ligands. Thus, further studies are needed for the characterization of the ligand-RAGE-interaction. These studies will provide a rationale for the development of new therapeutic approaches for accelerated atherosclerosis in diabetes mellitus.
Herz 07/2004; 29(5):504-509. · 0.92 Impact Factor
-
Shi-Fang Yan,
Ravichandran Ramasamy,
Loredana G Bucciarelli, Thoralf Wendt,
Larisse K Lee,
Barry I Hudson,
David M Stern,
Evanthia Lalla,
Shi DU Yan,
Ling Ling Rong,
Yoshifumi Naka,
Ann Marie Schmidt
[show abstract]
[hide abstract]
ABSTRACT: The complications of diabetes are myriad and represent a rising cause of morbidity and mortality, particularly in the Western world. The update of the Diabetes Control and Clinical Trials Group/Epidemiology of Diabetes Interventions and Complications Research Group (DCCT/EDIC) suggested that previous strict control of hyperglycaemia was associated with reduced carotid atherosclerosis compared to conventional treatment, even after levels of glycosylated haemoglobin between the two treatment groups became indistinguishable. These intriguing findings prompt the key question, why does the blood vessel 'remember'? This review focuses on the hypothesis that the ligand/RAGE axis contributes importantly to glycaemic 'memory'. Studies in rodent models of diabetes suggest that blockade or genetic modification of RAGE suppress diabetes-associated progression of atherosclerosis, exaggerated neointimal expansion consequent to acute arterial injury, and cardiac dysfunction. We propose that therapeutic RAGE blockade will intercept maladaptive diabetes-associated memory in the vessel wall and provide cardiovascular protection in diabetes.
Diabetes & Vascular Disease Research 06/2004; 1(1):10-20. · 2.12 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Although there is clear evidence from experimental diabetic neuropathy (DN) models that the multiple pathways involved in neuronal degeneration cause overproduction of reactive oxygen species, oxidative stress, and cellular dysfunction, therapeutic approaches addressing these mechanisms have not yet provided a basis for a successful treatment of patients with DN. This review discusses the current knowledge on the pathomechanisms of unchecked reactive oxygen species accumulation, implications for specific treatment, and the need for carefully designed experimental studies and clinical trials closing the gap between promising results in experimental DN and its implementation into a pathogenetically oriented treatment.
Current Diabetes Reports 01/2004; 3(6):452-8. · 2.50 Impact Factor
-
Barry I Hudson,
Loredana G Bucciarelli, Thoralf Wendt,
Taichi Sakaguchi,
Evanthia Lalla,
Wu Qu,
Yan Lu,
Larisse Lee,
David M Stern,
Yoshifumi Naka,
Ravichandran Ramasamy,
Shi Du Yan,
Shi Fang Yan,
Vivette D'Agati,
Ann Marie Schmidt
[show abstract]
[hide abstract]
ABSTRACT: The glycation and oxidation of proteins/lipids leads to the generation of a new class of biologically active moieties, the advanced glycation endproducts (AGEs). Recent studies have elucidated that carboxymethyllysine (CML) adducts of proteins/lipids are a highly prevalent AGE in vivo. CML-modified adducts are signal transduction ligands of the receptor for AGE (RAGE), a member of the immunoglobulin superfamily. Importantly, CML-modified adducts accumulate in diverse settings. In addition to enhanced formation in settings of high glucose, these adducts form in inflammatory milieu. Studies performed both in vitro and in vivo have suggested that the proinflammatory/tissue destructive consequences of RAGE activation in the diabetic/inflamed environment may be markedly attenuated by blockade of the ligand-RAGE axis. Here, we will summarize the known consequences of RAGE activation in the tissues and highlight novel areas for therapeutic intervention in these disease states.
Archives of Biochemistry and Biophysics 11/2003; 419(1):80-8. · 2.93 Impact Factor
-
Thoralf Wendt,
Nozomu Tanji,
Jiancheng Guo,
Barry I Hudson,
Angelika Bierhaus,
Ravichandran Ramasamy,
Bernd Arnold,
Peter P Nawroth,
Shi Fang Yan,
Vivette D'Agati,
Ann Marie Schmidt
[show abstract]
[hide abstract]
ABSTRACT: Receptor for advanced glycation endproducts (RAGE) is a multi-ligand member of the immunoglobulin superfamily of cell surface molecules. Driven by rapid accumulation and expression of key ligands such as advanced glycation endproducts (AGE) and S100/calgranulins in diabetic tissues, upregulation and activation of RAGE magnifies cellular perturbation in tissues affected by hyperglycemia, such as the large blood vessels and the kidney. In the diabetic glomerulus, RAGE is expressed principally by glomerular visceral epithelial cells (podocytes). Blockade of RAGE in the hyperglycemic db/db mouse suppresses functional and structural alterations in the kidney, in the absence of alterations in blood glucose. Recent studies in homozygous RAGE null mice support a key role for RAGE in glomerular perturbation in diabetes. Importantly, beyond diabetes, studies in other settings of glomerulopathies support a critical RAGE-dependent pathway in podocytes linked to albuminuria, mesangial expansion, and glomerular sclerosis. A new paradigm is proposed in glomerular injury, and it is suggested that blockade of the RAGE axis may provide a novel means to prevent irreparable glomerular injury in diabetes and other sclerosing glomerulopathies.
Journal of the American Society of Nephrology 06/2003; 14(5):1383-95. · 9.66 Impact Factor
-
Stephan Schiekofer,
Martin Andrassy,
Jiang Chen,
Gottfried Rudofsky,
Jochen Schneider, Thoralf Wendt,
Norbert Stefan,
Per Humpert,
Andreas Fritsche,
Michael Stumvoll,
Erwin Schleicher,
Hans-Ulrich Häring,
Peter P Nawroth,
Angelika Bierhaus
[show abstract]
[hide abstract]
ABSTRACT: Twenty-three nondiabetic volunteers were divided into three groups. In group A (n = 9), the glucose infusion was adjusted to maintain blood glucose at 5 mmol/l (euglycemic clamp). In group B (n = 9), the glucose infusion was adjusted to maintain blood glucose at 10 mmol/l (hyperglycemic clamp) over 2 h. Group C consisted of five volunteers who were studied as the control group. Peripheral blood mononuclear cells (PBMCs) were isolated before and at the end of a 2-h clamp. In group C, PBMCs were isolated before and after 2 h without performing a clamp. The euglycemic clamp as well as "no clamp" had no effects on all parameters studied. In contrast, a significant increase in carboxymethyllysine (CML) content and p21(ras) and p42/44 mitogen-activated protein kinase (MAPK) phosphorylation was observed at the end of a 2-h hyperglycemic clamp. The nuclear factor (NF)-kappaB (but not Oct-1) binding activity increased significantly in the hyperglycemic clamp. Western blots confirmed NF-kappaB-p65-antigen translocation into the nucleus. IkappaBalpha did not change significantly in both groups. Hyperglycemia-mediated NF-kappaB activation and increase of CML content, p21(ras), and p42/44 MAPK phosphorylation was also seen in ex vivo-isolated PBMCs stimulated with 5 or 10 mmol/l glucose. Addition of insulin did not influence the results. Inhibition of activation of ras, MAPK, or protein kinase C blocked hyperglycemia-mediated NF-kappaB activation in ex vivo-isolated PBMCs stimulated with 10 mmol/l glucose. Similar data were obtained using an NF-kappaB-luciferase reporter plasmid. Therefore, we can conclude that an acute hyperglycemia-mediated mononuclear cell activation is dependent on activation of ras, p42/p44 MAPK phosphorylation, and subsequent NF-kappaB activation and results in transcriptional activity in PBMCs.
Diabetes 04/2003; 52(3):621-33. · 8.29 Impact Factor
-
Angelika Bierhaus,
Jutta Wolf,
Martin Andrassy,
Nicolas Rohleder,
Per M Humpert,
Dimitri Petrov,
Roman Ferstl,
Maximilian von Eynatten, Thoralf Wendt,
Gottfried Rudofsky,
Martina Joswig,
Michael Morcos,
Markus Schwaninger,
Bruce McEwen,
Clemens Kirschbaum,
Peter P Nawroth
[show abstract]
[hide abstract]
ABSTRACT: Little is known about the mechanisms converting psychosocial stress into cellular dysfunction. Various genes, up-regulated in atherosclerosis but also by psychosocial stress, are controlled by the transcription factor nuclear factor kappaB (NF-kappaB). Therefore, NF-kappaB is a good candidate to convert psychosocial stress into cellular activation. Volunteers were subjected to a brief laboratory stress test and NF-kappaB activity was determined in peripheral blood mononuclear cells (PBMC), as a window into the body and because PBMC play a role in diseases such as atherosclerosis. In 17 of 19 volunteers, NF-kappaB was rapidly induced during stress exposure, in parallel with elevated levels of catecholamines and cortisol, and returned to basal levels within 60 min. To model this response, mice transgenic for a strictly NF-kappaB-controlled beta-globin transgene were stressed by immobilization. Immobilization resulted in increased beta-globin expression, which could be reduced in the presence of the alpha1-adrenergic inhibitor prazosin. To define the role of adrenergic stimulation in the up-regulation of NF-kappaB, THP-1 cells were induced with physiological amounts of catecholamines for 10 min. Only noradrenaline resulted in a dose- and time-dependent induction of NF-kappaB and NF-kappaB-dependent gene expression, which depended on pertussis-toxin-sensitive G protein-mediated phosphophatidylinositol 3-kinase, Ras/Raf, and mitogen-activated protein kinase activation. Induction was reduced by alpha(1)- and beta-adrenergic inhibitors. Thus, noradrenaline-dependent adrenergic stimulation results in activation of NF-kappaB in vitro and in vivo. Activation of NF-kappaB represents a downstream effector for the neuroendocrine response to stressful psychosocial events and links changes in the activity of the neuroendocrine axis to the cellular response.
Proceedings of the National Academy of Sciences 03/2003; 100(4):1920-5. · 9.68 Impact Factor
-
Loredana G Bucciarelli, Thoralf Wendt,
Wu Qu,
Yan Lu,
Evanthia Lalla,
Ling Ling Rong,
Mouza T Goova,
Bernhard Moser,
Thomas Kislinger,
Daniel C Lee,
Yogita Kashyap,
David M Stern,
Ann Marie Schmidt
[show abstract]
[hide abstract]
ABSTRACT: Previous studies suggested that blockade of RAGE in diabetic apolipoprotein (apo) E-null mice suppressed early acceleration of atherosclerosis. A critical test of the potential applicability of RAGE blockade to clinical settings was its ability to impact established vascular disease. In this study, we tested the hypothesis that RAGE contributed to lesion progression in established atherosclerosis in diabetic apoE-null mice.
Male apoE-null mice, age 6 weeks, were rendered diabetic with streptozotocin or treated with citrate buffer. At age 14 weeks, certain mice were killed or treated with once-daily murine soluble RAGE or albumin; all mice were killed at age 20 weeks. Compared with diabetic mice at age 14 weeks, albumin-treated animals displayed increased atherosclerotic lesion area and complexity. In diabetic mice treated with sRAGE from age 14 to 20 weeks, lesion area and complexity were significantly reduced and not statistically different from those observed in diabetic mice at age 14 weeks. In parallel, decreased parameters of inflammation and mononuclear phagocyte and smooth muscle cell activation were observed.
RAGE contributes not only to accelerated lesion formation in diabetic apoE-null mice but also to lesion progression. Blockade of RAGE may be a novel strategy to stabilize atherosclerosis and vascular inflammation in established diabetes.
Circulation 12/2002; 106(22):2827-35. · 14.74 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The incidence and severity of atherosclerosis is increased in patients with diabetes. Indeed, accelerated macrovascular disease in diabetic patients has emerged as a leading cause of morbidity and mortality in the United States and worldwide. Multiple investigations have suggested that there are numerous potential contributory factors that underlie these observations. Our laboratory has focused on the contribution of receptor for advanced glycation endproducts (RAGE) and its proinflammatory ligands, advanced glycation endproducts (AGEs) and S100/calgranulins in vascular perturbation, manifested as enhanced atherogenesis or accelerated restenosis after angioplasty. In rodent models of diabetic complications, blockade of RAGE suppressed vascular hyperpermeability, accelerated atherosclerotic lesion area and complexity in diabetic apolipoprotein E-deficient mice, and prevented exaggerated neointimal formation in hyperglycemic fatty Zucker rats subjected to injury of the carotid artery. In this review, we summarize these findings and provide an overview of distinct mechanisms that contribute to the development of accelerated diabetic macrovascular disease. Insights into therapeutic strategies to prevent or interrupt these processes are presented.
Current Atherosclerosis Reports 06/2002; 4(3):228-37. · 2.66 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The major consequence of long-term diabetes is the increased incidence of disease of the vasculature. Of the underlying mechanisms leading to disease, the accumulation of advanced glycation end products (AGEs), resulting from the associated hyperglycemia, is the most convincing. Interaction of AGEs with their receptor, RAGE, activates numerous signaling pathways leading to activation of proinflammatory and procoagulatory genes. Studies in rodent models of macro- and microvascular disease have demonstrated that blockade of RAGE can prevent development of disease. These observations highlight RAGE as a therapeutic target for treatment of diabetic vascular disease.
Antioxidants and Redox Signaling 7(11-12):1588-600. · 8.46 Impact Factor
