Article

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

ABSTRACT

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.

Download full-text

Full-text

Available from: Ravi Ramasamy
  • Source
    • "Previous data also demonstrated that luteolin blocks the PI3K-AKT-NF-κB-ERK 1/2 pathway and attenuates the increase in ROS and elevates the Bcl-2/Bax ratio, leading to decreased apoptotic cell death (Zhou et al. 2011). As reported in the literature, the receptor for advanced glycation end products (RAGE) plays an important role as a cell-surface receptor for Aβ at the blood-brain barrier and in neurons and microglia (Yan et al. 1996, 2010; Zlokovic 2011; Origlia et al. 2010). The extracellular V domain of RAGE is the key domain in Aβ binding to RAGE (Sturchler et al. 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Alzheimer's disease (AD) is an age-related neurodegenerative disorder in which amyloid β (Aβ) peptide accumulates in the brain. The receptor for advanced glycation end product (RAGE) is a cellular binding site for Aβ peptide and mediates amyloid β-induced perturbations in cerebral vessels, neurons, and microglia in AD. Here, we identified a specific high-affinity RAGE inhibitor (APDTKTQ named RP-1) from a phage display library. RP-1 bound to RAGE and inhibited Aβ peptide-induced cellular stress in human neuroblastoma SH-SYSY cells in vitro. Three amino acids in RP-1 are identical to those in the Aβ peptide. RP-1 shows high homology to the 16-23 (KLVFFAED) regions in Aβ peptide and high-affinity RAGE. Functional analyses indicated that RP-1 significantly reduced the level of reactive oxygen species (ROS) and ROS products and that it enhanced catalase and glutathione peroxidase (GPx) activity. Furthermore, it inactivated caspase3 and caspase9 and inhibited the upregulation of RAGE, nuclear factor-κB (NF-κB), and beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) protein expression. In addition, RP-1 activated the PI3K/AKT signaling pathway, inhibiting the interaction between Bax and Bcl-2. Our data suggest that RP-1 is a potent RAGE blocker that effectively controls the progression of Aβ peptide-mediated brain disorders and that it may have potential as a disease-modifying agent for AD.
    Full-text · Article · Oct 2015 · Applied Microbiology and Biotechnology
  • Source
    • "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 "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Feb 2015 · Mechanisms of Ageing and Development
  • Source
    • "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]]. "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Dec 2014 · EJNMMI Research
Show more