Chemically oversulfated glycosaminoglycans are potent modulators of contact system activation and different cell signaling pathways. J Biol Chem 2010 Jul 23;285(30):22966-75
Date
04/27/2010Pubmed ID
20418371Pubmed Central ID
PMC2906290DOI
10.1074/jbc.M109.063735Scopus ID
2-s2.0-77953644228 (requires institutional sign-in at Scopus site) 52 CitationsAbstract
Contaminated heparin was associated with adverse reactions by activating the contact system. Chemically oversulfated/modified glycosaminoglycans (GAGs) consisting of heparan sulfate, dermatan sulfate, and chondroitin sulfate have been identified as heparin contaminants. Current studies demonstrated that each component of oversulfated GAGs was comparable with oversulfated chondroitin sulfate in activating the contact system. By testing a series of unrelated negatively charged compounds, we found that the contact system recognized negative charges rather than specific chemical structures. We further tested how oversulfated GAGs and contaminated heparins affect different cell signaling pathways. Our data showed that chemically oversulfated GAGs and contaminated heparin had higher activity than the parent compounds and authentic heparin, indicative of sulfation-dominant and GAG sequence-dependent activities in BaF cell-based models of fibroblast growth factor/fibroblast growth factor receptor, glial cell line-derived neurotrophic factor/c-Ret, and hepatocyte growth factor/c-Met signaling. In summary, these data indicate that contaminated heparins intended for blood anticoagulation not only activated the contact system but also modified different GAG-dependent cell signaling pathways.
Author List
Pan J, Qian Y, Zhou X, Lu H, Ramacciotti E, Zhang LMESH terms used to index this publication - Major topics in bold
AnimalsCell Line
Cell Proliferation
Dermatan Sulfate
Glycosaminoglycans
Heparin
Heparitin Sulfate
Humans
Intercellular Signaling Peptides and Proteins
Kallikreins
Receptors, Growth Factor
Signal Transduction
Thrombin