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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Atherosclerosis is a major global cause of morbidity and mortality, and diabetes patients are at increased risk of coronary heart disease development. Advanced glycation of proteins occurs in the body due to raised concentrations of reducing sugars and reactive oxygen species, and is a causal factor behind complications of diabetes. Glycated proteins, through alteration of protein structure and function, and from ligation with their receptors, lead to widespread vascular damage. The alpha-oxoaldehyde, methylglyoxal (MG) is the most reactive glycation precursor, and is increased in the blood of diabetes patients. There is debate about the triggering events leading to atherosclerosis, but the inflammatory action of glycated proteins, including those with MG adducts, through their receptor, RAGE, is a major candidate for initiating plaque formation. In addition glycation may cause cross-links on proteins of the extracellular matrix, stiffening arteries and 'trapping' other macromolecules. MG is also likely to form adducts on many other proteins, enzymes, lipids, DNA or RNA, changing their structure, and may disrupt enzyme activity, hormone regulation and immune function. In the latter context, MG disrupts function of the potent antigen presenting cells, dendritic cells. This effect may be a double edged sword: Poor control of infections may contribute to persistent inflammation, whilst inhibition of immune activation by dendritic cells may inhibit plaque progression. This review aims to present these ideas as a novel slant on the role of the glycation process in atherosclerosis.
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PMID:Advanced glycation: a novel outlook on atherosclerosis. 1822 Aug 6

Diabetic vascular complication is a leading cause of acquired blindness, end-stage renal failure, a variety of neuropathies and accelerated atherosclerosis, which could account for disabilities and high mortality rates in patients with diabetes. Although several hyperglycemia-elicited metabolic and hemodynamic derangements have been implicated in the pathogenesis of diabetic vascular complication, the process of formation and accumulation of advanced glycation end products (AGEs) and their mode of action are most compatible with the theory 'hyperglycemic memory'. Further, there is a growing body of evidence that AGEs and their receptor (RAGE) axis is involved in the pathogenesis of diabetic vascular complication. Indeed, the engagement of RAGE with AGEs is shown to elicit oxidative stress generation and subsequently evoke inflammatory responses in various types of cells, thus playing an important role in the development and progression of diabetic micro- and macroangiopathy. These observations suggest that down-regulation of RAGE expression or blockade of the RAGE downstream signaling may be a promising target for therapeutic intervention in diabetic vascular complication. In this review, we discuss several types of agents that could potentially inhibit RAGE expression or its downstream pathways and their therapeutic implications in diabetic vascular complication.
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PMID:Receptor for advanced glycation end products (RAGE): a novel therapeutic target for diabetic vascular complication. 1828 75

1. There is increasing evidence that advanced glycation end-products (AGEs) and their interaction with the receptor RAGE play a pivotal role in atherosclerosis, in particular in the setting of diabetes. 2. Previous studies have shown that inhibition of AGE accumulation and RAGE expression in diabetes by either reduction of the formation of AGEs or cross-link breakers was associated with reduced atherosclerosis and renal disease. Advanced glycation end-products bind to RAGE, thereby leading to activation of a range of inflammatory and fibrotic pathways causing tissue injury. Different splice variants of RAGE exist, including a soluble form that lacks the intracellular domain and fails to induce signal transduction. Therapeutic approaches using soluble RAGE as a decoy binding protein for circulating AGE have been effective in preventing externally induced arterial injury and atherosclerosis in the absence and presence of diabetes. 3. In order to delineate the role of RAGE in vascular disease in more detail, it was necessary to create RAGE(-/-) mice, as well as transgenic mice overexpressing RAGE in endothelial cells. It was shown that RAGE overexpression was associated with increased vascular injury, nephropathy and retinopathy. 4. In contrast, RAGE deletion was associated with partial vascular protection, such as reduced neointima formation after arterial denudation, as well as protection from diabetic nephropathy. The present review summarizes the evidence for RAGE being a pro-inflammatory and pro-fibrotic receptor. 5. Further studies are needed to delineate the effect of RAGE deletion and overexpression in diabetic macrovascular disease. Based on these findings, RAGE could be a potential therapeutic target in combating inflammatory vascular diseases, including diabetes-associated atherosclerosis.
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PMID:The AGE/RAGE axis in diabetes-accelerated atherosclerosis. 1829 Aug 73

Unifying mechanisms for the consequences of aging and chronic diabetes are coming to light with the identification that common to both settings is the production and accumulation of the largely irreversible Advanced Glycation Endproducts (AGEs). AGEs impart multiple consequences in the tissues; a key means by which they exert maladaptive effects is via their interaction with and activation of their chief cell surface receptor, Receptor for AGE or RAGE. Although the time course, rate and extent of AGE generation and accumulation in diabetes and aging may be distinct, unifying outcomes of the ligand-RAGE interaction in the vasculature and heart are linked to upregulation of inflammatory and tissue-destructive mechanisms. Consistent with these concepts, administration of the ligand-binding decoy of RAGE, soluble or sRAGE, suppresses early initiation and progression of atherosclerosis in diabetic mice; suppresses exaggerated neointimal expansion consequent to arterial injury; and mitigates the adverse impact of ischemia/reperfusion injury in the heart. Importantly, the RAGE ligand repertoire upregulated in these settings is not limited to AGEs. The key finding that RAGE was a multi-ligand receptor unified the concept that in diabetes and aging, innate and adaptive inflammatory mechanisms contribute to the pathogenesis of tissue injury. We conclude that antagonism of RAGE may reflect a novel and therapeutically logical and safe target in cardiovascular stress induced by aging and chronic diabetes.
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PMID:Receptor for Advanced Glycation Endproducts (RAGE): a formidable force in the pathogenesis of the cardiovascular complications of diabetes & aging. 1833 Dec 28

HMGB1/Amphoterin is a ubiquitous, highly conserved DNA-binding protein that can be also released to the extracellular space by various cell types. Extracellular HMGB1 regulates migratory responses of several cell types through binding to RAGE that communicates with the cytoskeleton to regulate cell motility. HMGB1-induced cell signalling has been associated with mechanisms of several diseases, including cancer, sepsis, rheumatoid arthritis, stroke and atherosclerosis. This article reviews the evidence linking the functional roles of HMGB1 to RAGE signalling. Furthermore, we discuss the molecular and cellular mechanisms that may explain the roles of HMGB1/RAGE in diverse disease processes.
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PMID:RAGE as a receptor of HMGB1 (Amphoterin): roles in health and disease. 1833 Dec 30

Advanced glycation end-products (AGEs) are generated in the diabetic milieu, as a result of chronic hyperglycemia and enhanced oxidative stress. These AGEs, via direct and receptor dependent pathways promote the development and progression of cardiovascular disease. AGEs accumulate at many sites of the body including the heart and large blood vessels in diabetes. These modified proteins interact with receptors such as RAGE to induce oxidative stress, increase inflammation by promoting NFkappaB activation and enhance extracellular matrix accumulation. These biological effects translate to accelerated plaque formation in diabetes as well as increased cardiac fibrosis with consequent effects on cardiac function. Strategies to reduce the ligation of AGEs to their receptors such as agents which reduce AGE accumulation, soluble RAGE which acts as a competitive antagonist to the binding of AGEs to RAGE and genetic deletions of RAGE appear to attenuate diabetes associated atherosclerosis. Benefits on cardiac dysfunction with these inhibitors of the AGE/RAGE axis are not as well characterised. In conclusion, therapeutic strategies targeting AGEs appear to have significant clinical potential, often in combination with currently used agents such as inhibitors of the renin-angiotensin system, to reduce the major burden of diabetes, its associated cardiovascular complications.
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PMID:The role of AGEs in cardiovascular disease. 1847 49

Steno-2 Study has previously shown that intensified multifactorial intervention reduces the risk of nonfatal cardiovascular disease in patients with type 2 diabetes. Further, in the recent follow-up study, intensive therapy was found to have sustained beneficial effects on cardiovascular events and death in this population. A similar outcome was reported in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT-EDIC) Research, which revealed that original intensive therapy reduced the risk of cardiovascular events to about 50% of that of conventional treatment in type 1 diabetic patients 11 years after the end of the trial, although glycosylated hemoglobin values in the two groups had almost converged during the follow-up periods. These two clinical studies strongly suggest that so-called 'metabolic memory' causes chronic vascular damage in diabetic patients, that are not easily reversed, even by subsequent, relatively good control of metabolic risk factors. Potential mechanisms for propagating this 'metabolic memory' are the non-enzymatic glycation of proteins. Indeed, the formation and accumulation of advanced glycation end products (AGEs) have been known to progress at an accelerated rate under diabetes, and there is accumulating evidence that AGEs-their receptor RAGE interaction elicits oxidative stress generation and subsequently evokes vascular inflammation, thus being involved in the pathogenesis of accelerated atherosclerosis in diabetes. Since renin-angiotensin system inhibitors or a lipid-lowering agent, atorvastatin, not only inhibit the AGE-signaling to inflammation, but also reduce serum levels of AGEs in type 2 diabetic patients, it is conceivable that the carry-over beneficial effects of multifactorial intervention on cardiovascular events and death in the follow-up Steno-2 Study could be ascribed, at least in part, to its inhibitory effects on AGE formation and/or the downstream-signaling pathways. Therefore, it is interesting to clarify whether circulating or skin AGE levels at the closure of Steno-2 Study could predict cardiovascular events at the end of the trial. This clinical investigation may provide us more information about whether blockade of the AGE-RAGE system is one of the mechanisms for sustained beneficial effects of multifactorial intervention on mortality in type 2 diabetes.
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PMID:Blockade of the advanced glycation end products (AGEs) and their receptor (RAGE) system is a possible mechanism for sustained beneficial effects of multifactorial intervention on mortality in type 2 diabetes. 1871 Jul 93

Healthy vascular function is primarily regulated by several factors including EDRF (endothelium-dependent relaxing factor), EDCF (endothelium-dependent contracting factor) and EDHF (endothelium-dependent hyperpolarizing factor). Vascular dysfunction or injury induced by aging, smoking, inflammation, trauma, hyperlipidaemia and hyperglycaemia are among a myriad of risk factors that may contribute to the pathogenesis of many cardiovascular diseases, such as hypertension, diabetes and atherosclerosis. However, the exact mechanisms underlying the impaired vascular activity remain unresolved and there is no current scientific consensus. Accumulating evidence suggests that the inflammatory cytokine TNF (tumour necrosis factor)-alpha plays a pivotal role in the disruption of macrovascular and microvascular circulation both in vivo and in vitro. AGEs (advanced glycation end-products)/RAGE (receptor for AGEs), LOX-1 [lectin-like oxidized low-density lipoprotein receptor-1) and NF-kappaB (nuclear factor kappaB) signalling play key roles in TNF-alpha expression through an increase in circulating and/or local vascular TNF-alpha production. The increase in TNF-alpha expression induces the production of ROS (reactive oxygen species), resulting in endothelial dysfunction in many pathophysiological conditions. Lipid metabolism, dietary supplements and physical activity affect TNF-alpha expression. The interaction between TNF-alpha and stem cells is also important in terms of vascular repair or regeneration. Careful scrutiny of these factors may help elucidate the mechanisms that induce vascular dysfunction. The focus of the present review is to summarize recent evidence showing the role of TNF-alpha in vascular dysfunction in cardiovascular disease. We believe these findings may prompt new directions for targeting inflammation in future therapies.
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PMID:Role of TNF-alpha in vascular dysfunction. 1911 93

Advanced glycation end product receptor (RAGE) interaction plays an important role in atherosclerosis. Although exogenously administered soluble form of RAGE (sRAGE) has been shown to suppress the development and progression of atherosclerosis in animals, the kinetics and role of endogenous sRAGE in humans are not fully understood. In this study, to clarify whether endogenous sRAGE could capture and efficiently eliminate RAGE ligands such as circulating AGEs and high-mobility group box-1 (HMGB-1), we investigated the correlation between sRAGE and RAGE ligands and examined independent determinants of serum levels of sRAGE in hypertensive humans. Two-hundred seventy-one consecutive nondiabetic outpatients with essential hypertension (83 male and 188 female; mean age, 76.5 +/- 9.2 years) underwent a complete history, physical examination, and determination of blood chemistries, including serum levels of sRAGE, AGEs, and HMGB-1. Univariate regression analysis showed that serum levels of sRAGE were associated with body mass index (r = -0.313, P < .0001), waist (r = -0.214, P < .0001), alanine aminotransferase (r = -0.172, P = .005), gamma-glutamyltranspeptidase (r = -0.213, P < .0001), 24-hour creatinine clearance (r = -0.348, P < .0001), B-type natriuretic peptide (r = 0.138, P = .027), tumor necrosis factor-alpha (r = 0.138, P = .002), and alcohol intake (r = -0.155, P = .010). By the use of multiple stepwise regression analyses, 24-hour creatinine clearance (P < .0001), gamma-glutamyltranspeptidase (P < .001), body mass index (P = .007), and tumor necrosis factor-alpha (P = .024) remained significant independently. The present study demonstrated for the first time that there was no significant correlation between serum levels of sRAGE and RAGE ligands such as circulating AGEs and HMGB-1 in hypertensive patients. Anthropometric and inflammatory variables and liver and renal function may be the determinants of endogenous sRAGE levels in nondiabetic hypertensive patients.
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PMID:Independent determinants of soluble form of receptor for advanced glycation end products in elderly hypertensive patients. 1921 61

The major complication of diabetes is accelerated atherosclerosis, the progression of which entails complex interactions between the modified low-density lipoproteins (LDL) and the cells of the arterial wall. Advanced glycation end product-modified-LDL (AGE-LDL) that occurs at high rate in diabetes contributes to diabetic atherosclerosis, but the underlying mechanisms are not fully understood. The aim of this study was to assess the direct effect of AGE-LDL on human vascular smooth muscle cells (hSMC) dysfunction. Cultured hSMC incubated (24 hrs) with human AGE-LDL, native LDL (nLDL) or oxidized LDL (oxLDL) were subjected to: (i) quantification of the expression of the receptors for modified LDL and AGE proteins (LRP1, CD36, RAGE) and estimation of lipid loading, (ii) determination of NADPH oxidase activity and reactive oxygen species (ROS) production and (iii) evaluation of the expression of monocyte chemoattractant protein-1 (MCP-1). The results show that exposure of hSMC to AGE-LDL (compared to nLDL) induced: (a) increased NADPH oxidase activity (30%) and ROS production (28%) by up-regulation of NOX1, NOX4, p22phox and p67phox expression, (b) accumulation of intracellular cholesteryl esters, (c) enhanced gene expression of LRP1 (160%) and CD36 (35%), and protein expression of LRP1, CD36 and RAGE, (d) increased MCP-1 gene expression (160%) and protein secretion (300%) and (e) augmented cell proliferation (30%). In conclusion, AGE-LDL activates hSMC (increasing CD36, LRP1, RAGE), inducing a pro-oxidant state (activation of NADPHox), lipid accumulation and a pro-inflammatory state (expression of MCP-1). These results may partly explain the contribution of AGE-LDL and hSMC to the accelerated atherosclerosis in diabetes.
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PMID:Effect of irreversibly glycated LDL in human vascular smooth muscle cells: lipid loading, oxidative and inflammatory stress. 1981 91


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