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Chemically oversulfated glycosaminoglycans are potent modulators of contact system activation and different cell signaling pathways.

ABSTRACT: 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.

SUBMITTER: Pan J

PROVIDER: S-EPMC2906290 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Chemically oversulfated glycosaminoglycans are potent modulators of contact system activation and different cell signaling pathways.

Pan Jing J Qian Yi Y Zhou Xiaodong X Lu Hong H Ramacciotti Eduardo E Zhang Lijuan L

The Journal of biological chemistry 20100423 30

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 ...[more]

PMID: 20418371

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Project description:The contact activation system (CAS) exerts effects on coagulation via multiple mechanisms, which modulate both the intrinsic and extrinsic coagulation cascades as well as fibrinolysis and platelet activation. While the effects of the CAS on blood coagulation measured as activated partial thromboplastin time shortening are well documented, genetic mutations that result in deficiencies in the expression of either plasma prekallikrein (PPK) or factor XII (FXII) are not associated with spontaneous bleeding or increased bleeding risk during surgery. Deficiencies in these proteins are often undiagnosed for decades and detected later in life during routine coagulation assays without an apparent clinical phenotype. Increased interest in the CAS as a potentially safe target for antithrombotic therapies has emerged, in large part, from studies on animal models with provoked thrombosis, which have shown that deficiencies in PPK or FXII can reduce thrombus formation without increasing bleeding. Gene targeting and pharmacological studies in healthy animals have confirmed that PPK and FXII blockade does not cause coagulopathies. These findings support the conclusion that CAS is not required for hemostasis. However, while deficiencies in FXII and PPK do not significantly affect bleeding associated with peripheral wounds, recent reports have demonstrated that these proteins can promote hemorrhage in the retina and brain. Intravitreal injection of plasma kallikrein (PKal) induces retinal hemorrhage and intracerebral injection of PKal increases intracranial bleeding. PPK deficiency and PKal inhibition ameliorates hematoma formation following cerebrovascular injury in diabetic animals. Moreover, both PPK and FXII deficiency are protective against intracerebral hemorrhage caused by tissue plasminogen activator-mediated thrombolytic therapy in mice with thrombotic middle cerebral artery occlusion. Thus, while the CAS is not required for hemostasis, its inhibition may provide an opportunity to reduce hemorrhage in the retina and brain. Characterization of the mechanisms and potential clinical implications associated with the effects of the CAS on hemorrhage requires further consideration of the effects of PPK and FXII on hemorrhage beyond their putative effects on coagulation cascades. Here, we review the experimental and clinical evidence on the effects of the CAS on bleeding and hemostatic mechanisms.

Project description:Mesenchymal stem cells (MSCs) are considered as an attractive source of cells for cartilage engineering due to their availability and capacity for expansion and multipotency. Differentiation of MSC into chondrocytes is crucial to successful cartilage regeneration and can be induced by various biological agents, including polysaccharides that participate in many biological processes through interactions with growth factors. Here, we hypothesize that growth factor-induced differentiation of MSC can be increased by chemically oversulfated marine polysaccharides. To test our hypothesis, human adipose tissue-derived MSCs (hATSCs) were cultured in pellets with transforming growth factor (TGF)-?1-supplemented chondrogenic medium containing either the polysaccharide GY785 DR or its oversulfated isoform GY785 DRS. Chondrogenesis was monitored by the measurement of pellet volume, quantification of DNA, collagens, glycosaminoglycans (GAGs), and immunohistological staining. Our data revealed an increase in pellet volume, total collagens, and GAG production with GY785 DRS and chondrogenic medium. The enhanced chondrogenic differentiation of hATSC was further demonstrated by the increased expression of several chondrogenic markers by real-time reverse transcription-polymerase chain reaction. In addition, surface plasmon resonance analyses revealed that TGF-?1 bound GY785 DRS with higher affinity compared to GY785 DR. In association with TGF-?1, GY785 DRS was found to upregulate the phosphorylation of extracellular signal-regulated kinase 1/2, indicating that oversulfated polysaccharide affects the mitogen activated protein kinase signaling activity. These results demonstrate the upregulation of TGF-?1-dependent stem cell chondrogenesis by a chemically oversulfated marine polysaccharide. This polysaccharide of marine origin is easily producible and therefore could be considered a promising additive to drive efficient and reliable MSC chondrogenesis for cartilage tissue engineering.

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Chemically oversulfated glycosaminoglycans are potent modulators of contact system activation and different cell signaling pathways.

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Chemically oversulfated glycosaminoglycans are potent modulators of contact system activation and different cell signaling pathways.

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