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The N-glycoform of sRAGE is the key determinant for its therapeutic efficacy to attenuate injury-elicited arterial inflammation and neointimal growth

Authors
 Hyun-Jin Tae ; Ji Min Kim ; Li Lin ; Edward G. Lakatta ; Mark I. Talan ; Rui-ping Xiao ; Yuan Chuan Lee ; David Browe ; Christopher H. Morrell ; Yinghua Zhang ; Rebecca A. Riebe ; Stefanie Cruschwitz ; John Pang ; Ismayil Ahmet ; Natalia Petrashevskaya ; Wen Wei ; Geng Li ; Noboru Tomiya ; Sungha Park 
Citation
 Journal of Molecular Medicine, Vol.91(12) : 1369~1381, 2013 
Journal Title
 Journal of Molecular Medicine 
ISSN
 0946-2716 
Issue Date
2013
Abstract
Signaling of the receptor for advanced glycation end products (RAGE) has been implicated in the development of injury-elicited vascular complications. Soluble RAGE (sRAGE) acts as a decoy of RAGE and has been used to treat pathological vascular conditions in animal models. However, previous studies used a high dose of sRAGE produced in insect Sf9 cells (sRAGESf9)and multiple injections to achieve the therapeutic outcome. Here, we explore whether modulation of sRAGE N-glycoform impacts its bioactivity and augments its therapeutic efficacy. We first profiled carbohydrate components of sRAGE produced in Chinese hamster Ovary cells (sRAGECHO) to show that a majority of its N-glycans belong to sialylated complex types that are not shared by sRAGESf9. In cell-based NF-κB activation and vascular smooth muscle cell (VSMC) migration assays, sRAGECHO exhibited a significantly higher bioactivity relative to sRAGESf9 to inhibit RAGE alarmin ligand-induced NF-κB activation and VSMC migration. We next studied whether this N-glycoform-associated bioactivity of sRAGECHO is translated to higher in vivo therapeutic efficacy in a rat carotid artery balloon injury model. Consistent with the observed higher bioactivity in cell assays, sRAGECHO significantly reduced injury-induced neointimal growth and the expression of inflammatory markers in injured vasculature. Specifically, a single dose of 3 ng/g of sRAGECHO reduced neointimal hyperplasia by over 70 %, whereas the same dose of sRAGESf9 showed no effect. The administered sRAGECHO is rapidly and specifically recruited to the injured arterial locus, suggesting that early intervention of arterial injury with sRAGECHO may offset an inflammatory circuit and reduce the ensuing tissue remodeling. Our findings showed that the N-glycoform of sRAGE is the key determinant underlying its bioactivity and thus is an important glycobioengineering target to develop a highly potent therapeutic sRAGE for future clinical applications.
URI
http://ir.ymlib.yonsei.ac.kr/handle/22282913/88498
DOI
10.1007/s00109-013-1091-4
Appears in Collections:
1. 연구논문 > 1. College of Medicine > Dept. of Internal Medicine
Yonsei Authors
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Link
 http://link.springer.com/article/10.1007%2Fs00109-013-1091-4
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