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: 11.09). 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.

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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.
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