sRAGE and Risk of Diabetes, Cardiovascular Disease, and Death

Selvin, Elizabeth; Halushka, Marc K.; Rawlings, Andreea M.; Hoogeveen, Ron C.; Ballantyne, Christie M.; Coresh, Josef; Astor, Brad C.

doi:10.2337/db12-1528

Cited by 153 publications

(144 citation statements)

References 45 publications

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“…Indeed, Falcone et al (24) reported that a decreased sRAGE level was correlated with a higher prevalence of cardiovascular risk factors and coronary artery disease in nondiabetic subjects. Furthermore, a low plasma level of sRAGE at baseline was independently associated with the risk of coronary heart disease and all-cause mortality during a median followup period of 18 years in a communitybased population (34). At present, the exact reason for the discrepant results about the relationship between sRAGE and cardiovascular disease is unclear.…”

Section: Discussionmentioning

confidence: 46%

Ratio of Serum Levels of AGEs to Soluble Form of RAGE Is a Predictor of Endothelial Function

et al. 2014

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OBJECTIVEAdvanced glycation end products (AGEs) and their specific receptor, the receptor for AGEs (RAGE), play an important role in atherosclerosis. Recently, a soluble form of RAGE (sRAGE) has been identified in human serum. However, the role of sRAGE in cardiovascular disease is still controversial. There is no information on the association between simultaneous measurements of AGEs and sRAGE and vascular function. In this study, we evaluated the associations between serum levels of AGEs and sRAGE, ratio of AGEs to sRAGE, and vascular function. RESEARCH DESIGN AND METHODSWe measured serum levels of AGEs and sRAGE and assessed vascular function by measurement of flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation in 110 subjects who underwent health examinations. Multivariate regression analyses were performed to identify factors associated with vascular function. RESULTSUnivariate regression analysis revealed that FMD correlated with age, BMI, systolic blood pressure, diastolic blood pressure, heart rate, triglycerides, HDL cholesterol, glucose, smoking pack-years, nitroglycerine-induced vasodilation, serum levels of AGEs and sRAGE, and ratio of AGEs to sRAGE. Multivariate analysis revealed that the ratio of AGEs to sRAGE remained an independent predictor of FMD, while serum level of AGEs alone or sRAGE alone was not associated with FMD. CONCLUSIONSThese findings suggest that sRAGE may have a counterregulatory mechanism that is activated to counteract the vasotoxic effect of the AGE-RAGE axis. The ratio of AGEs to sRAGE may be a new chemical biomarker of endothelial function.

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Section: Discussionmentioning

confidence: 46%

Ratio of Serum Levels of AGEs to Soluble Form of RAGE Is a Predictor of Endothelial Function

et al. 2014

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“…In some studies sRAGE levels were higher in coronary disease cases, or in those having a higher atherosclerotic burden, than in control subjects ( 33,34 ). In other studies concerning the same topic, exactly opposite results were obtained (35)(36)(37). Observed variations of sRAGE levels might refl ect both infl amma tory and compensatory mechanisms of pathological processes.…”

Section: Treatment With Therapeutically Relevant Statin Concentrationsmentioning

confidence: 60%

Statins stimulate the production of a soluble form of the receptor for advanced glycation end products

Quade-Lyssy

Kanarek

Baiersdörfer

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org complications, atherosclerosis, and Alzheimer's disease (AD) ( 1 ). Proteins and peptides like advanced glycation end products (AGEs), amyloid-␤ peptides (A ␤ s), S100/ calgranulin family members, and HMGB1 (amphoterin) have been identifi ed as ligands for RAGE ( 2 ). Diabetes is characterized by a high blood glucose level. This enhanced concentration of glucose is responsible for the nonenzymatic generation of AGEs. AGEs represent a heterogeneous group of proteins, lipids, and nucleic acids resulting from chemical reactions between reducing sugars and amino groups. Studies with animal models have shown that RAGE is the best known target for AGEs in the vasculature and it is well established that the AGE/RAGE interaction contributes to the progression of atherosclerotic plaques ( 3-5 ). Ligand/RAGE interaction induces activation of various pro-infl ammatory and pro-atherogenic mediators, such as the nuclear factor-B (NF-B)-dependent mediators vascular cell adhesion molecule-1, tumor necrosis factor-␣ , interleukin-6, and RAGE ( 6 ). Because RAGE itself is regulated by NF-B, this further increases its expression and promotes cellular dysfunction ( 7 ).Blockade of RAGE by using the soluble form of the receptor ameliorates the vascular complications of diabetes in animal models ( 8-10 ) and suppresses the accumulation of A ␤ s in the brain of an AD mouse model ( 11 ). These benefi cial effects of soluble RAGE are thought to be mediated by trapping ligands, thus preventing ligand binding of membrane-bound RAGE. The circulating soluble form of RAGE containing only the extracellular part of fulllength RAGE, is either produced by alternative splicing The type I transmembrane protein receptor for advanced glycation end products (RAGE), a member of the immunoglobulin superfamily, has been shown to play a crucial role in chronic infl ammatory diseases, late diabetic Press, August 21, 2013 DOI 10.1194 Statins stimulate the production of a soluble form of the receptor for advanced glycation end products Abbreviations: A ␤ , amyloid-␤ peptide; AD, Alzheimer's disease; AGE, advanced glycation end product; APP, amyloid precursor protein; esRAGE, endogenous secretory receptor for advanced glycation end products; FCS, fetal calf serum; LDS, lipid-defi cient serum; M ␤ CD, methyl-␤ -cyclodextrin; NF-B, nuclear factor-B; RAGE, receptor for advanced glycation end products; RNAi, RNA interference; siRNA, small interfering RNA; SQS, squalene synthase; sRAGE, shed receptor-the soluble form of the receptor for advanced glycation end products after proteolytic shedding of the full length receptor; ZA, zaragozic acid A . Published, JLR Papers in

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“…However, the complex equilibrium of membrane-bound RAGE, sRAGE, esRAGE, and RAGE ligands is anything but deciphered. Some investigators have reported a direct correlation between sRAGE concentrations and risk of diabetic and cardiovascular complications (16,17), while in a somewhat different population, decreased concentrations were associated with increased risk (18).…”

mentioning

confidence: 99%

Decrease in Circulating Concentrations of Soluble Receptors for Advanced Glycation End Products at the Time of Seroconversion to Autoantibody Positivity in Children With Prediabetes

et al. 2015

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OBJECTIVEDietary advanced glycation end products (AGEs) and their interactions with the receptor for AGEs (RAGE) may play a role in the pathogenesis of type 1 diabetes. This study set out to assess whether there is any association of circulating concentrations of soluble RAGE (sRAGE), AGEs, and their ratio with the appearance of diabetes-associated autoantibodies in children progressing to clinical diabetes. RESEARCH DESIGN AND METHODSSerum concentrations of sRAGE, N-«(carboxymethyl)lysine (CML) adducts, and the sRAGE/CML ratio were analyzed in children who progressed to type 1 diabetes. The samples were taken at four time points: before seroconversion, at the time of the first autoantibody-positive sample, at the time of the first sample positive for multiple (>2) autoantibodies, and close to the disease diagnosis. Samples of autoantibody-negative controls matched for age, sex, and HLA-conferred diabetes risk were analyzed at corresponding time points. RESULTSThe prediabetic children had higher sRAGE concentrations before seroconversion (P c = 0.03), at the appearance of multiple autoantibodies (P c = 0.008), and close to diagnosis (P c = 0.04). Close to diagnosis, the cases had lower CML concentrations than the controls (P c = 0.004). Prediabetic children had a higher sRAGE/CML ratio than the controls before seroconversion (P c = 0.008) and at diagnosis (P c < 0.001). CONCLUSIONSPrediabetic children have higher concentrations of sRAGE and a higher sRAGE/ CML ratio than healthy controls. Circulating sRAGE concentrations seem to decline with the appearance of diabetes-predictive autoantibodies in children progressing to type 1 diabetes. The higher sRAGE/CML ratio in prediabetic children may reflect a higher AGE scavenger capacity.

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sRAGE and Risk of Diabetes, Cardiovascular Disease, and Death

Cited by 153 publications

References 45 publications

Ratio of Serum Levels of AGEs to Soluble Form of RAGE Is a Predictor of Endothelial Function

Ratio of Serum Levels of AGEs to Soluble Form of RAGE Is a Predictor of Endothelial Function

Statins stimulate the production of a soluble form of the receptor for advanced glycation end products

Decrease in Circulating Concentrations of Soluble Receptors for Advanced Glycation End Products at the Time of Seroconversion to Autoantibody Positivity in Children With Prediabetes

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