Paraoxonase-2 regulates coagulation activation through endothelial tissue factor.

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, deficiency in mice promotes atherogenesis through incompletely understood mechanisms. Here, we show that deregulated redox regulation in deficiency causes vascular inflammation and abnormalities in blood coagulation. In unchallenged 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 deficiency in the vasculature. Isolated endothelial cells from mice display increased tissue factor (TF) activity in vitro. Coagulation times were shortened and platelet procoagulant activity increased in mice relative to wild-type controls. Coagulation abnormalities of mice were normalized by anti-TF treatment, demonstrating directly that TF increases coagulation. PON2 reexpression in endothelial cells by conditional reversal of the knockout cassette, restoration in the vessel wall using bone marrow chimeras, or treatment with the antioxidant -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.