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 and Sven Horke

Key points

  • Loss of anti-oxidative PON2 causes cardiovascular dysfunction and activates coagulation

  • PON2 predominantly controls redox-sensitive endothelial TF activation pathways


Oxidative stress and inflammation of the vessel wall contribute to pro-thrombotic states. The anti-oxidative 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 Pon2-/- 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 IL-6 levels- originates from Pon2-deficientcy in the vasculature. Isolated endothelial cells from Pon2-/- mice display increased tissue factor (TF) activity in vitro. Coagulation times were shortened and platelet procoagulant activity increased in Pon2-/- mice relative to WT controls. Coagulation abnormalities of Pon2-/- mice were normalized by anti-TF treatment, demonstrating directly that TF increases coagulation. PON2 re-expression in endothelial cells by conditional reversal of the knock-out Pon2 cassette, restoration in the vessel wall using bone marrow chimeras, or treatment with the anti-oxidant N-acetylcysteine normalized the pro-coagulant state. These experiments delineate a PON2 redox-dependent mechanism that regulates endothelial cell TF activity and prevents systemic coagulation activation and inflammation.

  • Submitted September 19, 2017.
  • Accepted January 30, 2018.