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Structural Requirements for the Procoagulant Activity of Nucleic Acids
Nucleic acids, especially extracellular RNA, are exposed following tissue- or vessel damage and have previously been shown to activate the intrinsic blood coagulation pathway in vitro and in vivo. Yet, no information on structural requirements for the procoagulant activity of nucleic acids is availa...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3511531/ https://www.ncbi.nlm.nih.gov/pubmed/23226277 http://dx.doi.org/10.1371/journal.pone.0050399 |
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author | Gansler, Julia Jaax, Miriam Leiting, Silke Appel, Bettina Greinacher, Andreas Fischer, Silvia Preissner, Klaus T. |
author_facet | Gansler, Julia Jaax, Miriam Leiting, Silke Appel, Bettina Greinacher, Andreas Fischer, Silvia Preissner, Klaus T. |
author_sort | Gansler, Julia |
collection | PubMed |
description | Nucleic acids, especially extracellular RNA, are exposed following tissue- or vessel damage and have previously been shown to activate the intrinsic blood coagulation pathway in vitro and in vivo. Yet, no information on structural requirements for the procoagulant activity of nucleic acids is available. A comparison of linear and hairpin-forming RNA- and DNA-oligomers revealed that all tested oligomers forming a stable hairpin structure were protected from degradation in human plasma. In contrast to linear nucleic acids, hairpin forming compounds demonstrated highest procoagulant activities based on the analysis of clotting time in human plasma and in a prekallikrein activation assay. Moreover, the procoagulant activities of the DNA-oligomers correlated well with their binding affinity to high molecular weight kininogen, whereas the binding affinity of all tested oligomers to prekallikrein was low. Furthermore, four DNA-aptamers directed against thrombin, activated protein C, vascular endothelial growth factor and nucleolin as well as the naturally occurring small nucleolar RNA U6snRNA were identified as effective cofactors for prekallikrein auto-activation. Together, we conclude that hairpin-forming nucleic acids are most effective in promoting procoagulant activities, largely mediated by their specific binding to kininogen. Thus, in vivo application of therapeutic nucleic acids like aptamers might have undesired prothrombotic or proinflammatory side effects. |
format | Online Article Text |
id | pubmed-3511531 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-35115312012-12-05 Structural Requirements for the Procoagulant Activity of Nucleic Acids Gansler, Julia Jaax, Miriam Leiting, Silke Appel, Bettina Greinacher, Andreas Fischer, Silvia Preissner, Klaus T. PLoS One Research Article Nucleic acids, especially extracellular RNA, are exposed following tissue- or vessel damage and have previously been shown to activate the intrinsic blood coagulation pathway in vitro and in vivo. Yet, no information on structural requirements for the procoagulant activity of nucleic acids is available. A comparison of linear and hairpin-forming RNA- and DNA-oligomers revealed that all tested oligomers forming a stable hairpin structure were protected from degradation in human plasma. In contrast to linear nucleic acids, hairpin forming compounds demonstrated highest procoagulant activities based on the analysis of clotting time in human plasma and in a prekallikrein activation assay. Moreover, the procoagulant activities of the DNA-oligomers correlated well with their binding affinity to high molecular weight kininogen, whereas the binding affinity of all tested oligomers to prekallikrein was low. Furthermore, four DNA-aptamers directed against thrombin, activated protein C, vascular endothelial growth factor and nucleolin as well as the naturally occurring small nucleolar RNA U6snRNA were identified as effective cofactors for prekallikrein auto-activation. Together, we conclude that hairpin-forming nucleic acids are most effective in promoting procoagulant activities, largely mediated by their specific binding to kininogen. Thus, in vivo application of therapeutic nucleic acids like aptamers might have undesired prothrombotic or proinflammatory side effects. Public Library of Science 2012-11-30 /pmc/articles/PMC3511531/ /pubmed/23226277 http://dx.doi.org/10.1371/journal.pone.0050399 Text en © 2012 Gansler et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Gansler, Julia Jaax, Miriam Leiting, Silke Appel, Bettina Greinacher, Andreas Fischer, Silvia Preissner, Klaus T. Structural Requirements for the Procoagulant Activity of Nucleic Acids |
title | Structural Requirements for the Procoagulant Activity of Nucleic Acids |
title_full | Structural Requirements for the Procoagulant Activity of Nucleic Acids |
title_fullStr | Structural Requirements for the Procoagulant Activity of Nucleic Acids |
title_full_unstemmed | Structural Requirements for the Procoagulant Activity of Nucleic Acids |
title_short | Structural Requirements for the Procoagulant Activity of Nucleic Acids |
title_sort | structural requirements for the procoagulant activity of nucleic acids |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3511531/ https://www.ncbi.nlm.nih.gov/pubmed/23226277 http://dx.doi.org/10.1371/journal.pone.0050399 |
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