Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation
Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation
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DOI：
10.1073/pnas.0608647104
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发表时间：
2007-04-10
影响因子：
11.1
通讯作者：
Preissner, Klaus T.
中科院分区：
文献类型：
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作者：
Kannemeier, Christian;Shibamiya, Aya;Preissner, Klaus T.
在血管损伤时，局部控制止血可防止危及生命的失血并确保伤口愈合。来自这些部位受损细胞的细胞内物质将暴露于血液成分，并可能导致血液凝固和病理性血栓形成。到目前为止，这一概念的功能和机械后果还不清楚。在这里，我们在体内和体外的证据表明，不同形式的真核和原核RNA作为血液凝固的促进剂。发现细胞外RNA增强血液凝固的接触相途径的蛋白酶（如因子XII和XI）的（自动）活化，两者都表现出强的RNA结合。此外，外源性RNA的管理引起了显着的促凝反应的兔子。在经历动脉血栓形成模型的小鼠中，发现细胞外RNA与富含纤维蛋白的血栓相关，并且用RNase（但不是IDNase）预处理显著延迟闭塞性血栓形成。因此，来源于受损或坏死细胞的胞外RNA，特别是在病理条件或严重组织损伤下，代表了长期寻找的天然“外来表面”，并为凝血作用中因子XII/XI诱导的接触活化/a提供了促凝血辅因子模板。因此，细胞外RNA揭示了使用RNA酶或相关治疗策略进行抗血栓干预的尚未识别的靶标。
Upon vascular injury, locally controlled haemostasis prevents lifethreatening blood loss and ensures wound healing. Intracellular material derived from damaged cells at these sites will become exposed to blood components and could contribute to blood coagulation and pathological thrombus formation. So far, the functional and mechanistic consequences of this concept are not understood. Here, we present in vivo and in vitro evidence that different forms of eukaryotic and prokaryotic RNA serve as promoters of blood coagulation. Extracellular RNA was found to augment (auto-)activation of proteases of the contact phase pathway of blood coagulation such as factors XII and XI, both exhibiting strong RNA binding. Moreover, administration of exogenous RNA provoked a significant procoagulant response in rabbits. In mice that underwent an arterial thrombosis model, extracellular RNA was found associated with fibrin-rich thrombi, and pretreatment with RNase (but not IDNase) significantly delayed occlusive thrombus formation. Thus, extracellular RNA derived from damaged or necrotic cells particularly under pathological conditions or severe tissue damage represents the long sought natural "foreign surface" and provides a procoagulant cofactor template for the factors XII/XI-induced contact activation/a in pl ifi cation of blood coagulation. Extracellular RNA thereby reveals a yet unrecognized target for antithrombotic intervention, using RNase or related therapeutic strategies.