1. Enzymatic lipid oxidation by eosinophils propagates coagulation, hemostasis, and thrombotic disease.
- Author
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Uderhardt S, Ackermann JA, Fillep T, Hammond VJ, Willeit J, Santer P, Mayr M, Biburger M, Miller M, Zellner KR, Stark K, Zarbock A, Rossaint J, Schubert I, Mielenz D, Dietel B, Raaz-Schrauder D, Ay C, Gremmel T, Thaler J, Heim C, Herrmann M, Collins PW, Schabbauer G, Mackman N, Voehringer D, Nadler JL, Lee JJ, Massberg S, Rauh M, Kiechl S, Schett G, O'Donnell VB, and Krönke G
- Subjects
- Adult, Aged, Animals, Arachidonate 12-Lipoxygenase genetics, Arachidonate 15-Lipoxygenase genetics, Atherosclerosis diagnosis, Atherosclerosis metabolism, Blotting, Western, Cells, Cultured, Eosinophil Cationic Protein metabolism, Humans, Hydroxyeicosatetraenoic Acids metabolism, Logistic Models, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Oxidation-Reduction, Phosphatidylethanolamines metabolism, Prospective Studies, Reverse Transcriptase Polymerase Chain Reaction, Risk Factors, Thrombin metabolism, Arachidonate 12-Lipoxygenase metabolism, Arachidonate 15-Lipoxygenase metabolism, Blood Coagulation, Eosinophils metabolism, Hemostasis, Lipids analysis, Thrombosis metabolism
- Abstract
Blood coagulation is essential for physiological hemostasis but simultaneously contributes to thrombotic disease. However, molecular and cellular events controlling initiation and propagation of coagulation are still incompletely understood. In this study, we demonstrate an unexpected role of eosinophils during plasmatic coagulation, hemostasis, and thrombosis. Using a large-scale epidemiological approach, we identified eosinophil cationic protein as an independent and predictive risk factor for thrombotic events in humans. Concurrent experiments showed that eosinophils contributed to intravascular thrombosis by exhibiting a strong endogenous thrombin-generation capacity that relied on the enzymatic generation and active provision of a procoagulant phospholipid surface enriched in 12/15-lipoxygenase-derived hydroxyeicosatetraenoic acid-phosphatidylethanolamines. Our findings reveal a previously unrecognized role of eosinophils and enzymatic lipid oxidation as regulatory elements that facilitate both hemostasis and thrombosis in response to vascular injury, thus identifying promising new targets for the treatment of thrombotic disease., (© 2017 Uderhardt et al.)
- Published
- 2017
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