Networks of enzymatically oxidized membrane lipids support calcium-dependent coagulation factor binding to maintain hemostasis
| Autor: | Alastair W. Poole, Charles L. Percy, Andrea Brancale, David A. Slatter, Salvatore Ferla, Philip R. Taylor, Jessica E. Molhoek, Anne O’Connor, Peter William Collins, Valerie B. O'Donnell, Samya Obaji, Phillip G. de Groot, Keith Allen-Redpath, Simon Arnett Jones, P. Vince Jenkins, Maceler Aldrovandi, Stefan Uderhardt, Christopher P. Thomas, Jochen A. Ackermann, Sirpa Rannikko, Daniel Farewell, Ginger L. Milne, Rolf T. Urbanus, Victoria J. Tyrrell, Gerhard Krönke, Sarah Nicol Lauder, Sohvi Hörkkö |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Adult
Male 0301 basic medicine Membrane lipids 030204 cardiovascular system & hematology Biology Biochemistry Article Cohort Studies Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Hydroxyeicosatetraenoic Acids Animals Humans Platelet Platelet activation Blood Coagulation Molecular Biology Phospholipids Aged Venous Thrombosis Calcium metabolism Hemostasis Innate immune system Cell Membrane Cell Biology Phosphatidylserine Lipoxygenases Middle Aged Models Theoretical Antiphospholipid Syndrome Platelet Activation R1 Blood Coagulation Factors Cell biology Mice Inbred C57BL Disease Models Animal lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4] 030104 developmental biology Coagulation chemistry beta 2-Glycoprotein I Calcium Female lipids (amino acids peptides and proteins) |
| Zdroj: | Lauder, S N, Allen-Redpath, K, Slatter, D A, Aldrovandi, M, O'Connor, A, Farewell, D, Percy, C L, Molhoek, J E, Rannikko, S, Tyrrell, V J, Ferla, S, Milne, G L, Poole, A W, Thomas, C P, Obaji, S, Taylor, P R, Jones, S A, de Groot, P G, Urbanus, R T, Hörkkö, S, Uderhardt, S, Ackermann, J, Vince Jenkins, P, Brancale, A, Krönke, G, Collins, P W & O'Donnell, V B 2017, ' Networks of enzymatically oxidized membrane lipids support calcium-dependent coagulation factor binding to maintain hemostasis ', Science Signaling, vol. 10, no. 507, eaan2787 . https://doi.org/10.1126/scisignal.aan2787 Science Signaling, 10, eaan2787 Science Signaling, 10(507) Science Signaling, 10, 507, pp. eaan2787 |
| ISSN: | 1945-0877 |
| Popis: | Item does not contain fulltext Blood coagulation functions as part of the innate immune system by preventing bacterial invasion, and it is critical to stopping blood loss (hemostasis). Coagulation involves the external membrane surface of activated platelets and leukocytes. Using lipidomic, genetic, biochemical, and mathematical modeling approaches, we found that enzymatically oxidized phospholipids (eoxPLs) generated by the activity of leukocyte or platelet lipoxygenases (LOXs) were required for normal hemostasis and promoted coagulation factor activities in a Ca(2+)- and phosphatidylserine (PS)-dependent manner. In wild-type mice, hydroxyeicosatetraenoic acid-phospholipids (HETE-PLs) enhanced coagulation and restored normal hemostasis in clotting-deficient animals genetically lacking p12-LOX or 12/15-LOX activity. Murine platelets generated 22 eoxPL species, all of which were missing in the absence of p12-LOX. Humans with the thrombotic disorder antiphospholipid syndrome (APS) had statistically significantly increased HETE-PLs in platelets and leukocytes, as well as greater HETE-PL immunoreactivity, than healthy controls. HETE-PLs enhanced membrane binding of the serum protein beta2GP1 (beta2-glycoprotein 1), an event considered central to the autoimmune reactivity responsible for APS symptoms. Correlation network analysis of 47 platelet eoxPL species in platelets from APS and control subjects identified their enzymatic origin and revealed a complex network of regulation, with the abundance of 31 p12-LOX-derived eoxPL molecules substantially increased in APS. In summary, circulating blood cells generate networks of eoxPL molecules, including HETE-PLs, which change membrane properties to enhance blood coagulation and contribute to the excessive clotting and immunoreactivity of patients with APS. |
| Databáze: | OpenAIRE |
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