期刊
BLOOD
卷 131, 期 19, 页码 2161-2172出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2017-09-807040
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资金
- Center for Thrombosis and Hemostasis Mainz (BMBF) [01E01003, TRPA11i]
- Center for Translational Vascular Biology Mainz
- Gerhard and Martha Rottger Foundation
- German Research Foundation [DO1289/6-1]
- US Department of Defense [W81XWH-12-2-0091]
- Humboldt Foundation
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 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 interleukin-6 levels, originates from Pon2 deficiency 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 wild-type controls. Coagulation abnormalities of Pon2(-/-) 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.
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