Paraoxonase-2 regulates coagulation activation through endothelial tissue factor

Julia Ebert, Petra Wilgenbus, John F. Teiber, Kerstin Jurk, Kathrin Schwierczek, Mareike Döhrmann, Ning Xia, Huige Li, Lisa Spiecker, Wolfram Ruf, Sven Horke

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Oxidative stress and inflammation of the vessel wall contribute to prothrombotic states. The antioxidative protein paraoxonase-2 (PON2) shows reduced expression in human atherosclerotic plaques and endothelial cells in particular. Supporting a direct role for PON2 in cardiovascular diseases, Pon2 deficiency in mice promotes atherogenesis through incompletely understood mechanisms. Here, we show that deregulated redox regulation in Pon2 deficiency causes vascular inflammation and abnormalities in blood coagulation. In unchallenged Pon22/2 mice, we find increased oxidative stress and endothelial dysfunction. Bone marrow transplantation experiments and studies with endothelial cells provide evidence that increased inflammation, indicated by circulating interleukin-6 levels, originates from Pon2 deficiency in the vasculature. Isolated endothelial cells from Pon22/2 mice display increased tissue factor (TF) activity in vitro. Coagulation times were shortened and platelet procoagulant activity increased in Pon22/2 mice relative to wild-type controls. Coagulation abnormalities of Pon22/2 mice were normalized by anti-TF treatment, demonstrating directly that TF increases coagulation. PON2 reexpression in endothelial cells by conditional reversal of the knockout Pon2 cassette, restoration in the vessel wall using bone marrow chimeras, or treatment with the antioxidant N-acetylcysteine normalized the procoagulant state. These experiments delineate a PON2 redox-dependent mechanism that regulates endothelial cell TF activity and prevents systemic coagulation activation and inflammation.

Original languageEnglish (US)
Pages (from-to)2161-2172
Number of pages12
JournalBlood
Volume131
Issue number19
DOIs
StatePublished - May 10 2018

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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  • Cite this

    Ebert, J., Wilgenbus, P., Teiber, J. F., Jurk, K., Schwierczek, K., Döhrmann, M., Xia, N., Li, H., Spiecker, L., Ruf, W., & Horke, S. (2018). Paraoxonase-2 regulates coagulation activation through endothelial tissue factor. Blood, 131(19), 2161-2172. https://doi.org/10.1182/blood-2017-09-807040