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Background: Recent cohort studies suggested that serum levels of soluble Receptor for Advanced Glycation End-products (sRAGE) are associated with the risk of cardiovascular disease. We hypothesized that sRAGE levels are associated with subclinical atherosclerosis in a racially and ethnically diverse population., Methods and Results: 828 stroke-free participants from the Northern Manhattan Study (mean age 71.1±8.7yrs; 64% Hispanic, 19% black, and 17% white) underwent high-resolution carotid B-mode ultrasound to measure carotid plaque (present in 62% of subjects) and intima-media thickness (IMT) (mean Total=0.96±0.10 mm). Serum sRAGE was measured by ELISA and associations tested between sRAGE with IMT and plaque presence. Soluble RAGE levels were not associated with plaque presence or IMT after adjusting for sociodemographic, vascular risk factors and medication use. Stratification by race-ethnicity did not reveal any associations with carotid IMT or plaque., Conclusion: In the present study, sRAGE levels were not associated with carotid atherosclerosis., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: The objective of this cross-sectional analysis was to investigate the relation between two major high-density lipoprotein cholesterol (HDL-C) subfractions (HDL2-C and HDL3-C) and carotid plaque in a population based cohort., Methods: We evaluated 988 stroke-free participants (mean age 66 ± 8 years; 40% men; 66% Hispanic and 34% Non-Hispanic) with available data on HDL subfractions using precipitation method and carotid plaque area and thickness assessed by a high-resolution 2D ultrasound. The associations between HDL-C subfractions and plaque measurements were analyzed by quantile regression., Results: Plaque was present in 56% of the study population. Among those with plaque, the mean ± SD plaque area was 19.40 ± 20.46 mm² and thickness 2.30 ± 4.45 mm. The mean ± SD total HDL-C was 46 ± 14 mg/dl, HDL2-C 14 ± 8 mg/dl, and HDL3-C 32 ± 8 mg/dl. After adjusting for demographics and vascular risk factors, there was an inverse association between HDL3-C and plaque area (per mg/dl: beta = -0.26 at the 75th percentile, p = 0.001 and beta = -0.32 at the 90th percentile, p = 0.02). A positive association was observed between HDL2-C and plaque thickness (per mg/dl; beta = 0.02 at the 90% percentile, p = 0.003). HDL-C was associated with plaque area (per mg/dl: beta = -0.18 at the 90th percentile, p = 0.01), but only among Hispanics., Conclusion: In our cohort we observed an inverse association between HDL3-C and plaque area and a positive association between HDL2-C and plaque thickness. HDL-C subfractions may have different contributions to the risk of vascular disease. More studies are needed to fully elucidate HDL-C anti-atherosclerotic functions in order to improve HDL-based treatments in prevention of vascular disease and stroke., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

RAGE, the multiligand receptor of the immunoglobulin superfamily of cell surface molecules, is implicated in innate and adaptive immunity. Complement component C1q serves roles in complement activation and antibody-independent opsonization. Using soluble forms of RAGE (sRAGE) and RAGE-expressing cells, we determined that RAGE is a native C1q globular domain receptor. Direct C1q-sRAGE interaction was demonstrated with surface plasmon resonance (SPR), with minimum K(d) 5.6 μM, and stronger binding affinity seen in ELISA-like experiments involving multivalent binding. Pull-down experiments suggested formation of a receptor complex of RAGE and Mac-1 to further enhance affinity for C1q. C1q induced U937 cell adhesion and phagocytosis was inhibited by antibodies to RAGE or Mac-1. These data link C1q and RAGE to the recruitment of leukocytes and phagocytosis of C1q-coated material., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: Serum levels of the soluble receptor for advanced glycation end-products (sRAGE) have been associated with risk of cardiovascular disease. We hypothesized that sRAGE levels are associated with subclinical cerebrovascular disease in an ethnically diverse population., Methods: Clinically stroke-free participants in the multi-ethnic Northern Manhattan Study (NOMAS) underwent brain MRI to quantify subclinical brain infarcts (SBI) and white matter hyperintensity volume (WMHV) (n = 1102). Serum levels of sRAGE were measured by ELISA. Logistic and multiple linear regression were employed to estimate associations of sRAGE with SBI and WMHV, after adjusting for demographics and vascular risk factors., Results: Median sRAGE levels were significantly lower in Hispanics (891.9 pg/ml; n = 708) and non-Hispanic blacks (757.4 pg/ml; n = 197) than in non-Hispanic whites (1120.5 pg/ml; n = 170), and these differences remained after adjusting for other risk factors. Interactions were observed by race-ethnicity between sRAGE levels and MRI measurements, including for SBI in Hispanics (p = 0.04) and WMHV among blacks (p = 0.03). In Hispanics, increasing sRAGE levels were associated with a lower odds of SBI, with those in the upper sRAGE quartile displaying a 50% lower odds of SBI after adjusting for sociodemographic and vascular risk factors (p = 0.05). Among blacks, those in the upper quartile of sRAGE had a similarly reduced increased risk of SBI (p = 0.06) and greater WMHV (p = 0.04)., Conclusion: Compared to whites, Hispanics and blacks have significantly lower sRAGE levels, and these levels were associated with more subclinical brain disease. Taken together, these findings suggest sRAGE levels may be significantly influence by ethnicity. Further studies of sRAGE and stroke risk, particularly in minorities, are warranted., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Objective: A link between periodontal infections and an increased risk for vascular disease has been demonstrated. Porphyromonas gingivalis, a major periodontal pathogen, localizes in human atherosclerotic plaques, accelerates atherosclerosis in animal models and modulates vascular cell function. The receptor for advanced glycation endproducts (RAGE) regulates vascular inflammation and atherogenesis. We hypothesized that RAGE is involved in P. gingivalis's contribution to pro-atherogenic responses in vascular endothelial cells., Methods and Results: Murine aortic endothelial cells (MAEC) were isolated from wild-type C57BL/6 or RAGE-/- mice and were infected with P. gingivalis strain 381. P. gingivalis 381 infection significantly enhanced expression of RAGE in wild-type MAEC. Levels of pro-atherogenic advanced glycation endproducts (AGEs) and monocyte chemoattractant protein 1 (MCP-1) were significantly increased in wild-type MAEC following P. gingivalis 381 infection, but were unaffected in MAEC from RAGE-/- mice or in MAEC infected with DPG3, a fimbriae-deficient mutant of P. gingivalis 381. Consistent with a role for oxidative stress and an AGE-dependent activation of RAGE in this setting, both antioxidant treatment and AGE blockade significantly suppressed RAGE gene expression and RAGE and MCP-1 protein levels in P. gingivalis 381-infected human aortic endothelial cells (HAEC)., Conclusion: The present findings implicate for the first time the AGE-RAGE axis in the amplification of pro-atherogenic responses triggered by P. gingivalis in vascular endothelial cells., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

The receptor for advanced glycation end-products (RAGE) is expressed to enhance degrees in human atherosclerotic plaques and co-localizes with inflammatory and pro-oxidant mediators in the vulnerable regions of the plaque. Previous studies highlighted a number of variants in the gene encoding the receptor, including a Gly to Ser substitution at amino acid 82 within the ligand-binding domain of RAGE. The Ser82 allele enhanced ligand-binding affinity and increased ligand-stimulated generation of inflammatory mediators in transfected cells and human monocytes compared to the common RAGE Gly82 allele. Thus it was logical to test the hypothesis that increased prevalence of the Gly82Ser polymorphism was associated with cardiovascular events in the Framingham offspring study (n=1632). Our analyses revealed that the Gly82Ser RAGE polymorphism did not demonstrate any association with the incidence of cardiovascular disease in diabetic or non-diabetic subjects (Gly82 96%, Ser82 4%). Analysis of specific manifestations of cardiovascular disease, including coronary heart disease (CHD), cardiovascular disease (CVD), myocardial infarction (MI) and ischemic disease (ISD) revealed no association with RAGE genotype. Further studies are required on other more prevalent genetic variants of RAGE and cardiovascular disease.

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.