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

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...

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Published in:	Journal of molecular medicine (Berlin, Germany) Vol. 91; no. 12; pp. 1369 - 1381
Main Authors:	Tae, Hyun-Jin, Kim, Ji Min, Park, Sungha, Tomiya, Noboru, Li, Geng, Wei, Wen, Petrashevskaya, Natalia, Ahmet, Ismayil, Pang, John, Cruschwitz, Stefanie, Riebe, Rebecca A., Zhang, Yinghua, Morrell, Christopher H., Browe, David, Lee, Yuan Chuan, Xiao, Rui-ping, Talan, Mark I., Lakatta, Edward G., Lin, Li
Format:	Journal Article
Language:	English
Published:	Berlin/Heidelberg Springer Berlin Heidelberg 01-12-2013 Springer Nature B.V
Subjects:	Animals Arthritis - drug therapy Arthritis - metabolism Arthritis - pathology Biomarkers - metabolism Biomedical and Life Sciences Biomedicine Carotid Arteries - drug effects Carotid Arteries - metabolism Carotid Arteries - pathology Cell Movement - drug effects CHO Cells Cricetinae Cricetulus Disease Models, Animal Enzyme Activation - drug effects Glycosylation Human Genetics Humans Internal Medicine Ligands Male Molecular Medicine Muscle, Smooth, Vascular - drug effects Muscle, Smooth, Vascular - metabolism Neointima - drug therapy Neointima - metabolism NF-kappa B - metabolism Original Article Rats Receptor for Advanced Glycation End Products Receptors, Immunologic - administration & dosage Receptors, Immunologic - metabolism Recombinant Proteins - administration & dosage Recombinant Proteins - metabolism Sf9 Cells Therapeutic window N-glycoform Arterial inflammation sRAGE Arterial injury Neointimal hyperplasia
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Summary:	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 (sRAGE Sf9 )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 (sRAGE CHO ) to show that a majority of its N-glycans belong to sialylated complex types that are not shared by sRAGE Sf9 . In cell-based NF-κB activation and vascular smooth muscle cell (VSMC) migration assays, sRAGE CHO exhibited a significantly higher bioactivity relative to sRAGE Sf9 to inhibit RAGE alarmin ligand-induced NF-κB activation and VSMC migration. We next studied whether this N-glycoform-associated bioactivity of sRAGE CHO 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, sRAGE CHO significantly reduced injury-induced neointimal growth and the expression of inflammatory markers in injured vasculature. Specifically, a single dose of 3 ng/g of sRAGE CHO reduced neointimal hyperplasia by over 70 %, whereas the same dose of sRAGE Sf9 showed no effect. The administered sRAGE CHO is rapidly and specifically recruited to the injured arterial locus, suggesting that early intervention of arterial injury with sRAGE CHO 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. Key message The specific N-glycoform modification is the key underlying sRAGE bioactivity Markedly reduced sRAGE dose to attenuate neointimal hyperplasia and inflammation Provide a molecular target for glycobioengineering of sRAGE as a therapeutic protein Blocking RAGE alarmin ligands during acute injury phase offsets neointimal growth
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Equal contributors
ISSN:	0946-2716 1432-1440
DOI:	10.1007/s00109-013-1091-4