Paraoxonase-2 regulates coagulation activation through endothelial tissue factor
Paraoxonase-2 regulates coagulation activation through endothelial tissue factor
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DOI：
10.1182/blood-2017-09-807040
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发表时间：
2018-05-10
期刊：
影响因子：
20.3
通讯作者：
Horke, Sven
中科院分区：
文献类型：
--
作者：
Ebert, Julia;Wilgenbus, Petra;Horke, Sven
血管壁的氧化应激和炎症会导致血栓前状态。抗氧化蛋白对氧磷酶 2 (PON2) 在人类动脉粥样硬化斑块和内皮细胞中的表达量尤其降低。小鼠体内 Pon2 缺乏会通过尚不完全了解的机制促进动脉粥样硬化形成，这支持了 PON2 在心血管疾病中的直接作用。在这里，我们发现 Pon2 缺乏症中氧化还原调节失调会导致血管炎症和凝血异常。在未受到攻击的 Pon2(-/-) 小鼠中，我们发现氧化应激和内皮功能障碍增加。骨髓移植实验和内皮细胞研究提供的证据表明，循环白细胞介素 6 水平表明炎症增加源于脉管系统中的 Pon2 缺陷。来自 Pon2(-/-) 小鼠的分离内皮细胞在体外表现出组织因子 (TF) 活性增加。与野生型对照相比，Pon2(-/-) 小鼠的凝血时间缩短，血小板促凝血活性增加。 Pon2(-/-) 小鼠的凝血异常通过抗 TF 治疗而正常化，直接证明 TF 增加凝血。通过条件性逆转敲除的 Pon2 盒、使用骨髓嵌合体修复血管壁或用抗氧化剂 N-乙酰半胱氨酸治疗使促凝血状态正常化，在内皮细胞中重新表达 PON2。这些实验描绘了 PON2 氧化还原依赖性机制，可调节内皮细胞 TF 活性并防止全身凝血激活和炎症。
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.