The RAGE Axis A Fundamental Mechanism Signaling Danger to the Vulnerable Vasculature

Division of Surgical Science, Department of Surgery, Columbia University, 630 W 168th St, P&S 17-401, New York, NY 10032, USA.
Circulation Research (Impact Factor: 11.02). 03/2010; 106(5):842-53. DOI: 10.1161/CIRCRESAHA.109.212217
Source: PubMed


The immunoglobulin superfamily molecule RAGE (receptor for advanced glycation end product) transduces the effects of multiple ligands, including AGEs (advanced glycation end products), advanced oxidation protein products, S100/calgranulins, high-mobility group box-1, amyloid-beta peptide, and beta-sheet fibrils. In diabetes, hyperglycemia likely stimulates the initial burst of production of ligands that interact with RAGE and activate signaling mechanisms. Consequently, increased generation of proinflammatory and prothrombotic molecules and reactive oxygen species trigger further cycles of oxidative stress via RAGE, thus setting the stage for augmented damage to diabetic tissues in the face of further insults. Many of the ligand families of RAGE have been identified in atherosclerotic plaques and in the infarcted heart. Together with increased expression of RAGE in diabetic settings, we propose that release and accumulation of RAGE ligands contribute to exaggerated cellular damage. Stopping the vicious cycle of AGE-RAGE and RAGE axis signaling in the vulnerable heart and great vessels may be essential in controlling and preventing the consequences of diabetes.

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Article: The RAGE Axis A Fundamental Mechanism Signaling Danger to the Vulnerable Vasculature

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    • "Dietary advanced glycation end products (dAGEs) are known to contribute to increased oxidant stress and inflammation, which are linked to the recent epidemics of diabetes mellitus (DM) and cardiovascular disease (CVD). The receptor for AGE, defined as RAGE, is a cell-surface molecule that belongs to the immunoglobulin superfamily and binds many ligands, including AGE products (Yan et al., 2010). The interactions "
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    ABSTRACT: In stark contrast to many other blood biomarkers, including a variety of inflammatory cytokines, the main factors affecting sRAGE variation in the general human population are virtually unknown. We examined the contribution of age, body composition, and putative genetic sources to the interindividual variation of sRAGE. Its plasma levels were measured in 1557 apparently healthy individuals from 359 nuclear families. Statistical analysis revealed that all the aforementioned factors are statistically significantly associated with sRAGE levels. The levels of sRAGE consistently decreased with age (R = −0.264, p = <0.001) and with the indices of obesity, such as BMI. However, of special interest was the highly significant and previously not reported independent correlation with fat free mass (p < 0.001). The putative genetic effects explained 0.291 ± 0.089 of sRAGE variation and were solely responsible for the phenotypic correlations with the obesity phenotypes (genetic correlations, −0.22 ± 0.09 and −0.33 ± 0.09). Taken together, these data suggest that although genetically determined to a substantial degree, the sRAGE levels also depend on age and obesity, which in turn, increase the risk for a variety of pathological conditions associated with sRAGE. Clearly, identifying the metabolic pathways and specific genetic factors is the next important stage in this research area.
    Mechanisms of Ageing and Development 02/2015; 145. DOI:10.1016/j.mad.2015.01.001 · 3.40 Impact Factor
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    • "Receptor for advanced glycation end products (RAGE) is a multi-ligand receptor that plays an important role in the initiation and progression of atherosclerotic plaque and in mediating vascular inflammation in a variety of conditions [[1],[2]]. It is constitutively expressed in low levels on smooth muscle cells and endothelial cells in vascular endothelium, and the expression of RAGE increases in the vascular wall in response to a number of stimuli including hyperlipidemia and hyperglycemia [[3]]. "
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    ABSTRACT: Background Receptor for advanced glycated end product (RAGE) expression is a prominent feature of atherosclerosis. We have previously shown in apoE null mice uptake of a radiolabeled anti-RAGE antibody in atherosclerotic plaque and now evaluate RAGE-directed imaging to identify advanced plaques in a large animal model. Methods Nine hyperlipidemic (HL) pigs were injected with 603.1 ± 129.5 MBq of 99mTc-anti-RAGE F(ab′)2, and after 6 h (blood pool clearance), they underwent single-photon emission computed tomography/computed tomography (SPECT/CT) imaging of the neck, thorax, and hind limbs. Two HL pigs received 99mTc non-immune IgG F(ab′)2, and three farm pigs were injected with 99mTc-anti-RAGE F(ab′)2. After imaging, the pigs were euthanized. The aorta from the root to bifurcation was dissected, and the innominates, proximal carotids, and coronaries were dissected and counted, stained for H&E and RAGE, and AHA-classified. Results On pathology, 24% of the arterial segments showed AHA class III or IV lesions, and these lesions were confined almost exclusively to coronaries and carotids with % stenosis from 15% to 65%. Scatter plots of %ID/g for class III/IV vs. I/II lesions showed almost complete separation. Focal vascular uptake of tracer visualized on SPECT scans corresponded to class III/IV lesions in the coronary and carotid vessels. In addition, uptake in the hind limbs was noted in the HL pigs and corresponded to RAGE staining of small arteries in the muscle sections. Correlations for the vascular lesions were r = 0.747, P = 0.001 for %ID vs. %ID/g and r = 0.83, P = 0.002 for %ID/g vs. % RAGE staining. Conclusions Uptake of radiolabeled anti-RAGE antibody in coronary and carotid fibroatheroma and in the small arteries of the hind limbs in a relevant large animal model of atherosclerosis supports the important role of RAGE in atherosclerosis and peripheral artery disease as a target for imaging and treatment.
    EJNMMI Research 12/2014; 4(1):26. DOI:10.1186/s13550-014-0026-6
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    • "Collectively these and previous studies indicate that the effects of RAGE on T cell differentiation involves events in T cell differentiation proximal to STAT signaling. We compared Erk signaling in RAGE−/− and WT T cells and did not identify a difference in this signaling molecule, but evidence from other experimental systems have shown a role of RAGE-heparin sulfate and RAGE-HMGB1 complexes on cell signaling [12], [13], [14]. Signaling through RAGE involves interactions between the FH1 domain of mammalian Diaphanous-1 that interacts with the cytoplasmic tail of RAGE and can involve several intermediaries including NF-κB, MAPKs, PI3K/Akt, Rho GTPases, Jak/STAT, and Src family kinases [15]. "
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    ABSTRACT: The receptor for glycation end products (RAGE) has been previously implicated in shaping the adaptive immune response. RAGE is expressed in T cells after activation and constitutively in T cells from patients with diabetes. The effects of RAGE on adaptive immune responses are not clear: Previous reports show that RAGE blockade affects Th1 responses. To clarify the role of RAGE in adaptive immune responses and the mechanisms of its effects, we examined whether RAGE plays a role in T cell activation in a Th2 response involving ovalbumin (OVA)-induced asthma in mice. WT and RAGE deficient wild-type and OT-II mice, expressing a T cell receptor specific for OVA, were immunized intranasally with OVA. Lung cellular infiltration and T cell responses were analyzed by immunostaining, FACS, and multiplex bead analyses for cytokines. RAGE deficient mice showed reduced cellular infiltration in the bronchial alveolar lavage fluid and impaired T cell activation in the mediastinal lymph nodes when compared with WT mice. In addition, RAGE deficiency resulted in reduced OT-II T cell infiltration of the lung and impaired IFNγ and IL-5 production when compared with WT mice and reduced infiltration when transferred into WT hosts. When cultured under conditions favoring the differentiation of T cells subsets, RAGE deficient T cells showed reduced production of IFNγ but increased production of IL-17. Our data show a stimulatory role for RAGE in T activation in OVA-induced asthma. This role is largely mediated by the effects of RAGE on T cell proliferation and differentiation. These findings suggest that RAGE may play a regulatory role in T cell responses following immune activation.
    PLoS ONE 04/2014; 9(4):e95678. DOI:10.1371/journal.pone.0095678 · 3.23 Impact Factor
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