Modulation of Protein C Activation by Histones, Platelet Factor 4, and Heparinoids New Insights Into Activated Protein C Formation
Modulation of Protein C Activation by Histones, Platelet Factor 4, and Heparinoids New Insights Into Activated Protein C Formation
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DOI：
10.1161/atvbaha.113.302236
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发表时间：
2014-01-01
影响因子：
8.7
通讯作者：
Poncz, Mortimer
中科院分区：
文献类型：
--
作者：
Kowalska, M. Anna;Zhao, Guohua;Poncz, Mortimer
β-组蛋白在晚期脓毒症中是有害的。活化蛋白C（aPC）和肝素均可逆转其作用。在这里，我们研究了组蛋白是否可以以类似于另一种带正电荷的分子血小板因子4的方式调节aPC的产生，以及类肝素如何调节aPC的产生。方法和结果-我们测量了组蛋白、血小板因子4和类肝素对aPC形成的体外和体内作用，活化部分凝血活酶时间和小鼠存活率。在体外，组蛋白和血小板因子4都影响凝血酶/血栓调节蛋白aPC的产生，遵循钟形曲线，峰值>5倍增强。类肝素使这些曲线发生了明显的偏移。输注组蛋白、血小板因子4和类肝素后的小鼠aPC生成研究支持体外数据。重要的是，虽然普通肝素和2-O，3-O-乙酰肝素都逆转了高剂量组蛋白输注的致死率，只有小鼠用2-O，3-O-乙酰肝素治疗证明了纠正活化部分凝血活酶时间，并有显着水平的aPC. Conclusions，我们的数据提供了一个新的上下文模型，组蛋白如何影响aPC的产生，以及如何类肝素治疗可能是有益的败血症。这些研究为控制aPC形成的复杂相互作用提供了新的见解，并提出了一种新型的治疗干预策略。
Objective-Histones are detrimental in late sepsis. Both activated protein C (aPC) and heparin can reverse their effect. Here, we investigated whether histones can modulate aPC generation in a manner similar to another positively charged molecule, platelet factor 4, and how heparinoids (unfractionated heparin or oxygen-desulfated unfractionated heparin with marked decrease anticoagulant activity) may modulate this effect.Approach and Results-We measured in vitro and in vivo effects of histones, platelet factor 4, and heparinoids on aPC formation, activated partial thromboplastin time, and murine survival. In vitro, histones and platelet factor 4 both affect thrombin/thrombomodulin aPC generation following a bell-shaped curve, with a peak of >5-fold enhancement. Heparinoids shift these curves rightward. Murine aPC generation studies after infusions of histones, platelet factor 4, and heparinoids supported the in vitro data. Importantly, although unfractionated heparin and 2-O, 3-O desulfated heparin both reversed the lethality of high-dose histone infusions, only mice treated with 2-O, 3-O desulfated heparin demonstrated corrected activated partial thromboplastin times and had significant levels of aPC.Conclusions-Our data provide a new contextual model of how histones affect aPC generation, and how heparinoid therapy may be beneficial in sepsis. These studies provide new insights into the complex interactions controlling aPC formation and suggest a novel therapeutic interventional strategy.