Networks of enzymatically oxidized membrane lipids support calcium-dependent coagulation factor binding to maintain hemostasis

Beitrag in einer Fachzeitschrift


Details zur Publikation

Autorinnen und Autoren: Lauder SN, Allen-Redpath K, Slatter DA, Aldrovandi M, O'Connor A, Farewell D, Percy CL, Molhoek JE, Rannikko S, Tyrrell VJ, Ferla S, Milne GL, Poole AW, Thomas CP, Obaji S, Taylor PR, Jones SA, De Groot PG, Urbanus RT, Horkko S, Uderhardt S, Ackermann J, Jenkins PV, Brancale A, Krönke G, Collins PW, O'Donnell VB
Zeitschrift: Science Signaling
Jahr der Veröffentlichung: 2017
Band: 10
Heftnummer: 507
ISSN: 1937-9145


Abstract


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 Ca2+- 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 ?2GP1 (?2-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.



FAU-Autorinnen und Autoren / FAU-Herausgeberinnen und Herausgeber

Krönke, Gerhard Prof. Dr. med.
Medizinische Klinik 3 - Rheumatologie und Immunologie


Einrichtungen weiterer Autorinnen und Autoren

Cardiff University
Oulun Yliopisto / University of Oulo
St. James's Hospital
Universiteit Utrecht (UU) / Utrecht University
University of Bristol
Vanderbilt University


Zitierweisen

APA:
Lauder, S.N., Allen-Redpath, K., Slatter, D.A., Aldrovandi, M., O'Connor, A., Farewell, D.,... O'Donnell, V.B. (2017). Networks of enzymatically oxidized membrane lipids support calcium-dependent coagulation factor binding to maintain hemostasis. Science Signaling, 10(507). https://dx.doi.org/10.1126/scisignal.aan2787

MLA:
Lauder, Sarah N., et al. "Networks of enzymatically oxidized membrane lipids support calcium-dependent coagulation factor binding to maintain hemostasis." Science Signaling 10.507 (2017).

BibTeX: 

Zuletzt aktualisiert 2018-05-10 um 02:16