Endothelial Protein C Receptor
Endothelial Protein C Receptor
复制标题
内皮蛋白C受体
作者：
C. Esmon;Jun Xu;Jian;Dongfeng Qu;Zolton Laszik;G. Ferrell;D. Stearns;Shichiro Kurosawa;F. Taylor;N. Esmon
简介 蛋白 C 抗凝途径在血液凝固反应的负调节中发挥着关键作用。该途径由凝血酶触发，这使得该系统能够作为“按需”机制来限制对损伤的凝血反应。具体而言，抗凝反应的强度与生成的凝血酶水平成正比。1 该途径的临床重要性可通过与该途径成员缺陷相关的严重血栓并发症来说明。2-4 当凝血酶与血栓调节蛋白 (TM)5 结合时，蛋白 C 途径启动（图 1）。内皮表面构成蛋白C激活的主要位点。凝血酶-TM 复合物是蛋白 C 的有效激活剂，但它很少或没有激活血小板或凝块纤维蛋白原的能力。因此，TM作为凝血酶的分子开关，包括凝血酶的大分子特异性和生理功能。当 C 蛋白与内皮细胞 C 蛋白受体 (EPCR) 结合时，C 蛋白活化会增强。6 内皮细胞 C 蛋白受体通过增加凝血酶-TM 复合物对 C 蛋白的亲和力来增强 C 蛋白活化。6-8 并非所有 C 蛋白活化复合物都涉及 EPCR，因为该蛋白在微循环中的水平较低。9 凝血酶-TM 复合物会被 C 蛋白抑制剂 10 和抗凝血酶 11 迅速灭活（图 1，底部）。一旦形成活化蛋白 C (APC)，它就会通过蛋白水解作用使两种关键的凝血辅助因子（因子 Va 和 VIIIa,12,13）失活，从而进一步限制凝血酶的形成。活化的蛋白 C 通过在 Arg506 处裂解而使因子 Va 失活，导致活性快速但不完全丧失，而 Arg306.12 在 Arg306 处裂解导致因子 Va 完全失活。蛋白 S 通过增加 APC 对膜表面 14-16 的亲和力并通过改变因子 Va 蛋白水解裂解的特异性（从而增强在 Arg306 处的裂解）作为此过程的辅助因子。 Arg306 不会显着调节 Arg506 的裂解。17 此外，蛋白 S 阻断因子 Xa 保护因子 Va 免遭 APC 失活的能力，并且在因子 IXa-因子 VIIIa 复合物失活中具有类似的功能。 17 此外，与因子 V 结合，蛋白 S 增强 APC 失活因子 VIII18,19 的能力（图 1，中）。最近，在了解 S 蛋白如何实现这些功能方面取得了进展。具体来说，当蛋白 S 与 APC 结合时，从 APC 活性位点到膜表面的距离减少约 1 nm。20 这种距离的减少可能是蛋白 S 能够选择性增加 Arg306 切割率的原因。这一结论是基于这样的观察：在不存在蛋白 S 的情况下，蛋白 C 嵌合体的膜表面与其活性位点之间的距离与蛋白 S-APC 复合物相似。21 对于嵌合体，蛋白 S 既不影响到膜表面的距离，也不影响因子 Va 中 Arg306 的裂解速率。此外，嵌合体和蛋白 S-APC 复合物在 Arg306 处的裂解速率几乎相同。 21 与大多数丝氨酸蛋白酶不同，APC 对血浆蛋白酶抑制剂的抑制具有抵抗力，其循环半衰期约为 15 分钟。 22 半衰期由以下血浆蛋白酶抑制剂的抑制决定：α1-抗胰蛋白酶、23 蛋白 C 抑制剂、24 和 α2-巨球蛋白25（图 1，底部）。每种都有助于 APC 抑制。在蛋白 S 或蛋白 C 完全缺乏的婴儿中观察到的危及生命的血栓并发症明显表明了该途径的临床重要性。2 在总蛋白 C 缺乏的情况下，这些血栓并发症最常见表现为皮肤微血管血栓形成（暴发性紫癜）。这些病变可以通过输注蛋白 C 来预防，但如果患者体内的蛋白 C 水平降低到较低水平，这些病变就会再次出现。蛋白 C 和蛋白 S 杂合性缺陷更为常见，蛋白 C 缺乏的频率较高，每 300 人中就有 1 人发生。3,4 单独的蛋白 C 或蛋白 S 杂合性缺陷是血栓形成的中等危险因素。然而，与其他危险因素结合起来，这些缺陷会大大增加血栓形成的风险。3,4 静脉血栓形成最常见的已知危险因素 APC 抵抗也与蛋白 C 途径有关。活化的蛋白 C 通常首先在 Arg506 处裂解，然后在 Arg306 处裂解，从而使因子 Va 失活。12,17,26 APC 抗性最常见的基础是因子 V 的二态性，导致 Arg506 被 Gln 取代。这种取代使该键能够抵抗 APC 的裂解。27 这种形式的因子 V 也称为因子 V Leiden，因为缺陷的分子基础是在该城市发现的。28 由于突变，因子 V Leiden 失活需要在 Arg306 处裂解，这是一个相对缓慢的过程。幸运的是，如前所述，蛋白 S 刺激 Arg306.17 处的裂解。这一观察结果可能解释了蛋白 S 缺乏与因子 V Leiden 结合导致血栓形成风险大幅增加的原因之一。蛋白 C 激活复合物（尤其是 TM）的缺陷也可能导致血栓形成风险。最近，Öhlin 等人发现 TM 中的突变和多态性似乎与心肌梗塞或静脉血栓形成的风险增加有关。29,30 Ireland 等人31 在 104 名心肌梗塞患者中，有 5 名发现了 TM 基因 5' 调控区的改变。这些突变可能会降低 TM 表达并增加心肌梗塞的风险。31 104 名年龄匹配的对照个体中只有 1 人患有任何这些突变。 TM 突变还可导致小鼠血栓形成。32 总而言之，这些观察结果为得出以下结论提供了坚实的临床基础：该通路的成员对于凝血系统的充分负调节至关重要。
Introduction The protein C anticoagulant pathway plays a critical role in the negative regulation of the blood clotting response. The pathway is triggered by thrombin, which allows the system to serve as an “on-demand” mechanism for limiting the coagulation response to injury. Specifically, the magnitude of the anticoagulant response is proportional to the level of thrombin generated.1 The clinical importance of the pathway is illustrated by the severe thrombotic complications associated with deficiencies of members of the pathway.2-4 The protein C pathway is initiated when thrombin binds to thrombomodulin (TM)5 (Fig. 1). The surface of the endothelium constitutes the main site for protein C activation. The thrombin-TM complex is a potent activator of protein C, but it has little or no ability to activate platelets or clot fibrinogen. Therefore, TM serves as a molecular switch for thrombin, including thrombin’s macromolecular specificity and physiological function. Protein C activation is enhanced when protein C binds to the endothelial cell protein C receptor (EPCR).6 Endothelial cell protein C receptor augments protein C activation by increasing the affinity of the thrombin-TM complex for protein C.6-8 Not all protein C activation complexes involve EPCR since the levels of this protein are low in the microcirculation.9 The thrombin-TM complex is rapidly inactivated by the protein C inhibitor10 and antithrombin11 (Fig. 1, bottom). Once activated protein C (APC) is formed, it proteolytically inactivates two critical blood clotting cofactors, factors Va and VIIIa,12,13 thereby limiting further thrombin formation. Activated protein C inactivates factor Va by cleaving at Arg506, which results in rapid but incomplete loss of activity, and Arg306.12 Cleavage at Arg306 results in complete inactivation of factor Va. Protein S serves as a cofactor for this process by increasing the affinity of APC for the membrane surface14-16 and by changing the specificity of the proteolytic cleavage of factor Va, which enhances cleavage at Arg306 without significantly modulating cleavage at Arg506.17 In addition, protein S blocks the ability of factor Xa to protect factor Va from inactivation by APC and has a similar function in the inactivation of the factor IXa-factor VIIIa complex.17 Furthermore, in combination with factor V, protein S enhances the ability of APC to inactivate factor VIII18,19 (Fig. 1, middle). Recently, there have been advances in understanding how protein S accomplishes these functions. Specifically, when protein S binds to APC, the distance from the active site of APC to the membrane surface is decreased about 1 nm.20 This decrease in distance is probably responsible for the ability of protein S to selectively increase the cleavage rate at Arg306. This conclusion is based on the observation that a protein C chimera has been prepared that, in the absence of protein S, has a distance between the membrane surface and its active site similar to that of the protein S-APC complex.21 With the chimera, protein S influences neither the distance to membrane surface nor the rate of cleavage of Arg306 in factor Va. Furthermore, the rate of cleavage at Arg306 for the chimera and the protein S-APC complex are almost identical.21 Unlike most serine proteases, APC is resistant to inhibition by plasma proteinase inhibitors and circulates with a half-life of approximately 15 minutes.22 The half-life is determined by inhibition with the following plasma protease inhibitors: α1-antitrypsin,23 protein C inhibitor,24 and α2-macroglobulin25 (Fig. 1, bottom). Each contributes to APC inhibition. The clinical importance of this pathway is evident by the life-threatening thrombotic complications observed in infants with complete deficiencies of protein S or protein C.2 In the case of total protein C deficiency, these thrombotic complications are most commonly manifested as microvascular thrombosis of the skin (purpura fulminans). These lesions can be prevented by infusion of protein C, but they reappear if the protein C levels in the patient are allowed to decrease to low levels. Heterozygous deficiencies of protein C and protein S are more common with the frequency of protein C deficiency, occurring in 1 in 300 individuals.3,4 Heterozygous deficiencies of protein C or protein S alone are modest risk factors for thrombosis. In combination with other risk factors, however, these deficiencies substantially increase thrombotic risk.3,4 The most common known risk factor for venous thrombosis, APC resistance, is also linked to the protein C pathway. Activated protein C normally inactivates factor Va by first cleaving at Arg506, followed by cleaving at Arg306.12,17,26 The most common basis for APC resistance is a dimorphism in factor V, which results in replacement of Arg506 with Gln. This substitution renders this bond resistant to cleavage by APC.27 This form of factor V is also termed factor V Leiden, because the molecular basis of the defect was identified in that city.28 As a result of the mutation, factor V Leiden inactivation requires cleavage at Arg306, which is a relatively slow process. Fortunately, as mentioned previously, protein S stimulates cleavage at Arg306.17 This observation may account for one of the reasons that protein S deficiency in combination with factor V Leiden results in a substantial increase in risk of thrombosis. Deficiencies in the protein C activation complex, most specifically TM, could also contribute to thrombotic risk. Recently, Öhlin et al identified mutations and polymorphisms in TM that appear to be associated with increased risk of myocardial infarction or venous thrombosis.29,30 Ireland et al31 identified alterations in the 5’ regulatory region of the TM gene in 5 of 104 patients with myocardial infarction. These mutations presumably reduce TM expression and contribute to the risk of myocardial infarction.31 Only 1 of 104 control, age matched individuals had any of these mutations. Mutations of TM also can lead to thrombosis in mice.32 Taken together, these observations provide a firm clinical basis to conclude that the members of this pathway are critical to adequate negative regulation of the blood clotting system.
登录
查看更多内容
DOI：
10.1073/pnas.83.10.3460
发表时间：
1986-05-01
影响因子：
11.1
作者：
NAWROTH, PP;HANDLEY, DA;STERN, DM
通讯作者：
STERN, DM
DOI：
10.1073/pnas.93.19.10212
发表时间：
1996-09-17
影响因子：
11.1
作者：
StearnsKurosawa, DJ;Kurosawa, S;Esmon, CT
通讯作者：
Esmon, CT
影响因子：
37.8
作者：
Z. Laszik;A. Mitro;F. Taylor;G. Ferrell;C. Esmon
通讯作者：
Z. Laszik;A. Mitro;F. Taylor;G. Ferrell;C. Esmon
体外灌注期间的内源性抗凝：肝素样抑制剂的产生。
DOI：
10.1152/ajpheart.1980.239.6.h742
发表时间：
1980
期刊：
The American journal of physiology
影响因子：
--
作者：
Murphy,TL;Walker,FJ;Taylor3rd,FB;Beller-Todd,B;Archer,LT;Sofer,SS;Hinshaw,LB
通讯作者：
Hinshaw,LB
影响因子：
15.9
作者：
COMP, PC;NIXON, RR;ESMON, CT
通讯作者：
ESMON, CT