DNase 1 Protects From Increased Thrombin Generation and Venous Thrombosis During Aging: Cross-Sectional Study in Mice and Humans.
DNase 1 Protects From Increased Thrombin Generation and Venous Thrombosis During Aging: Cross-Sectional Study in Mice and Humans.
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DNase 1在衰老过程中防止凝血酶生成增加和静脉血栓形成：小鼠和人类的横断面研究。
DOI：
10.1161/jaha.121.021188
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发表时间：
2022-01-18
影响因子：
5.4
通讯作者：
Dayal, Sanjana
中科院分区：
文献类型：
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作者：
Kumar, Rahul;Sonkar, Vijay K.;Swamy, Jagadish;Ahmed, Azaj;Sharathkumar, Anjali A.;Pierce, Gary L.;Dayal, Sanjana
人类衰老与血栓形成的风险增加有关，但其机制尚不清楚。我们假设衰老诱导中性粒细胞胞外陷阱的过氧化物依赖性释放，导致凝血酶生成和血栓形成。我们研究了C57 BL 6 J小鼠和同窝出生的谷胱甘肽过氧化物酶-1转基因和野生型小鼠在年轻（4个月）和老年（20个月）和健康队列的年轻（18-39岁）或中年/老年人（50-72岁）。在血浆中，我们测量了凝血酶生成潜力和中性粒细胞胞外陷阱的组分（无细胞DNA和瓜氨酸化组蛋白）。老年野生型小鼠凝血酶生成显著增加，而老年谷胱甘肽过氧化物酶-1转基因小鼠凝血酶生成减少。与年轻小鼠相比，老年野生型和老年谷胱甘肽过氧化物酶-1转基因小鼠的血浆细胞游离DNA水平升高相似。相反，瓜氨酸化组蛋白的血浆水平不随年龄或基因型而改变。体外中性粒细胞释放中性粒细胞外陷阱的情况在年轻和老年野生型或谷胱甘肽过氧化物酶-1转基因小鼠之间也相似。用DNA酶1处理血浆或小鼠可降低凝血酶生成的年龄相关性增加，DNA酶1处理可阻断老年C57 BL 6 J小鼠实验性静脉血栓的形成。同样，凝血酶生成潜力和血浆无细胞DNA（但不是瓜氨酸化组蛋白）在中年/老年人中较高，并且用DNA酶1处理血浆逆转了凝血酶生成的增加。我们得出结论，DNase 1限制凝血酶的产生，并在衰老过程中防止静脉血栓形成，可能是通过水解无细胞DNA。
Human aging is associated with increased risk of thrombosis, but the mechanisms are poorly defined. We hypothesized that aging induces peroxide‐dependent release of neutrophil extracellular traps that contribute to thrombin generation and thrombosis. We studied C57BL6J mice and littermates of glutathione peroxidase‐1 transgenic and wild‐type mice at young (4 month) and old (20 month) ages and a healthy cohort of young (18–39 years) or middle‐aged/older (50–72 years) humans. In plasma, we measured thrombin generation potential and components of neutrophil extracellular traps (cell‐free DNA and citrullinated histone). Aged wild‐type mice displayed a significant increase in thrombin generation that was decreased in aged glutathione peroxidase‐1 transgenic mice. Both aged wild‐type and aged glutathione peroxidase‐1 transgenic mice demonstrated similar elevation of plasma cell‐free DNA compared with young mice. In contrast, plasma levels of citrullinated histone were not altered with age or genotype. Release of neutrophil extracellular traps from neutrophils in vitro was also similar between young and aged wild‐type or glutathione peroxidase‐1 transgenic mice. Treatment of plasma or mice with DNase 1 decreased age‐associated increases in thrombin generation, and DNase 1 treatment blocked the development of experimental venous thrombi in aged C57BL6J mice. Similarly, thrombin generation potential and plasma cell‐free DNA, but not citrullinated histone, were higher in middle‐aged/older humans, and treatment of plasma with DNase 1 reversed the increase in thrombin generation. We conclude that DNase 1 limits thrombin generation and protects from venous thrombosis during aging, likely by hydrolyzing cell‐free DNA.