Hydrogen peroxide promotes aging-related platelet hyperactivation and thrombosis.
Hydrogen peroxide promotes aging-related platelet hyperactivation and thrombosis.
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DOI：
10.1161/circulationaha.112.000966
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发表时间：
2013-03-26
期刊：
影响因子：
37.8
通讯作者：
Lentz SR
中科院分区：
文献类型：
--
作者：
Dayal S;Wilson KM;Motto DG;Miller FJ Jr;Chauhan AK;Lentz SR
血栓形成事件的发生率随着年龄的增长而增加，但其机制尚不清楚。为了研究氧化应激在衰老过程中的促血栓形成作用，我们测试了一个假设，即过表达抗氧化酶谷胱甘肽过氧化物酶-1（Gpx 1）的老年小鼠免受实验性血栓形成的影响。首先在野生型C57 BL/6 J小鼠中检查对颈动脉血栓形成的易感性。光化学损伤小鼠颈动脉后，12月龄和18月龄小鼠的稳定闭塞时间明显短于4月龄小鼠（P<0.01）。与野生型小鼠不同，过表达Gpx 1（Gpx 1 Tg）的转基因小鼠在12或18个月龄时颈动脉闭塞的时间并没有缩短。野生型小鼠在12月龄或18月龄时下腔静脉结扎后也表现出对静脉血栓形成的易感性增加（P<0.05 vs 4月龄）。Gpx 1 Tg小鼠受到保护，免受这种与年龄相关的静脉血栓形成易感性增强。在野生型而非Gpx 1 Tg小鼠的凝血酶活化血小板中观察到了凝血酶依赖性血小板过度活化，表现为过氧化氢、纤维蛋白原结合和纤维蛋白原受体αIIbβ3活化增加（P<0.05）。聚乙二醇-过氧化氢酶或夹竹桃苷（NADPH氧化酶抑制剂）也可预防老年小鼠血小板活化反应增强。老年小鼠显示血小板内p47 phox和超氧化物歧化酶-1的表达增加，表明过氧化氢生成增加的机制途径。我们的研究结果表明，过氧化氢是一个关键的介导血小板过度活跃和增强血栓形成的易感性，在老年小鼠。
The incidence of thrombotic events increases during aging, but the mechanisms are not well understood. To investigate the prothrombotic role of oxidative stress during aging, we tested the hypothesis that aged mice overexpressing the antioxidant enzyme glutathione peroxidase-1 (Gpx1) are protected from experimental thrombosis. Susceptibility to carotid artery thrombosis was first examined in wild-type C57BL/6J mice. After photochemical injury of the carotid artery, the time to stable occlusion was significantly shorter in 12- and 18-month-old mice compared with 4-month-old mice (P<0.01). Unlike wild-type mice, transgenic mice overexpressing Gpx1 (Gpx1 Tg) did not exhibit shortened times to occlusion of the carotid artery at 12 or 18 months of age. Wild-type mice also exhibited increased susceptibility to venous thrombosis after inferior vena cava ligation at 12 or 18 months of age (P<0.05 versus 4 months of age). Gpx1 Tg mice were protected from this aging-related enhanced susceptibility to venous thrombosis. Age-dependent platelet hyperactivation, evidenced by increased hydrogen peroxide, fibrinogen binding, and activation of fibrinogen receptor αIIbβ3, was observed in thrombin-activated platelets from wild-type but not Gpx1 Tg mice (P<0.05). Enhanced platelet activation responses in aged mice were also prevented by polyethylene glycol-catalase or apocynin, an inhibitor of NADPH oxidase. Aged mice displayed increased intraplatelet expression of p47phox and superoxide dismutase-1, suggesting a mechanistic pathway for increased hydrogen peroxide generation. Our findings demonstrate that hydrogen peroxide is a key mediator of platelet hyperactivity and enhanced thrombotic susceptibility in aged mice.