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Title:
A long-acting PAI-1 inhibitor reduces thrombus formation
Author: Peng, Shuangzhou1,2,3; Xue, Guangpu1,2,6; Gong, Lihu1,2; Fang, Chao7,8; Chen, Jingfei5; Yuan, Cai4; Chen, Zhuo1,2; Yao, Lishan5; Furie, Bruce7; Huang, Mingdong1,2,4,7
Source: THROMBOSIS AND HAEMOSTASIS
Issued Date: 2017-07-01
Volume: 117, Issue:7, Pages:1338-1347
Keyword: PAI-1 inhibitor ; human serum albumin (HSA) ; thrombosis ; clot lysis
DOI: 10.1160/TH16-11-0891
DOC Type: Article
English Abstract: Plasminogen activator inhibitor 1 (PAI-1) is the main inhibitor of tissue-type and urokinase-type plasminogen activators (t/uPA) and plays an important role in fibrinolysis. Inhibition of PAI-1 activity prevents thrombosis and accelerates fibrinolysis, indicating that PAI-1 inhibitors may be used as effective antithrombotic agents. We previously designed a PAI-1 inhibitor (PAltrap) which is a variant of inactivated urokinase protease domain. In the present study, we fused PAltrap with human serum albumin (HSA) to develop a long-acting PAI-1 inhibitor. Unfortunately, the fusion protein PAltrap-HSA lost some potency compared to PAltrap (33 nM vs 10 nM). Guided by computational method, we carried out further optimisation to enhance inhibitory potency for PAI-1. The new PAltrap, denominated PAltrap(H37R)-HSA, which was the H37R variant of PAltrap fused to NSA, gave a six-fold improvement of IC50 (5 nM) for human active PAI-1 compared to PAIt-rap-NSA, and showed much longer plasma half-life (200-fold) compared to PAltrap. We further demonstrated that the PAltrap(H37R)-1 HSA inhibited exogenous or endogenous PAI-1 to promote fibrinolysis in fibrin-clot lysis assay. PAltrap(H37R)-HSA inhibits murine PAI-1 with IC50 value of 12 nM, allowing the inhibitor to be evaluated in murine models. Using an intravital microscopy, we demonstrated that PAIt-rap(H37R)-HSA blocks thrombus formation and platelet accumulation in vivo in a laser-induced vascular injury mouse model. Additionally, mouse tail bleeding assay showed that PAltrap(H37R)-HSA did not affect the global haemostasis. These results suggest that PAltrap(H37R)HSA have the potential benefit to prevent thrombosis and accelerates fibrinolysis.
WOS Headings: Science & Technology ; Life Sciences & Biomedicine
WOS Subject: Hematology ; Peripheral Vascular Disease
WOS Subject Extended: Hematology ; Cardiovascular System & Cardiology
WOS Keyword Plus: PLASMINOGEN-ACTIVATOR INHIBITOR-1 ; ARTERIAL THROMBOSIS ; IN-VIVO ; MICE ; THROMBOLYSIS ; STABILITY ; GENE ; FIBRINOLYSIS ; DEFICIENCY ; ANTAGONIST
Indexed Type: SCI
Funder: Natural Science Foundation of China(31370737 ; Strategic Priority Research Program of the CAS(XDA09030307) ; CAS/SAFEA International Partnership Program for Creative Research Teams ; Thrombosis and Hemostasis Societies of North America ; 31400637 ; 31570745 ; 31670739 ; U1405229)
Language: 英语
WOS ID: WOS:000404671700014
Citation statistics:
Content Type: 期刊论文
URI: http://ir.qibebt.ac.cn/handle/337004/9637
Appears in Collections:仿真与模拟团队_期刊论文

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description.institution: 1.Chinese Acad Sci, Fujian Inst Res Struct Matter, State Key Lab Struct Chem, Fuzhou, Fujian, Peoples R China
2.Chinese Acad Sci, Danish Chinese Ctr Proteases & Canc, Fujian Inst Res Struct Matter, Fuzhou, Fujian, Peoples R China
3.Fujian Agr & Forestry Univ, Coll Life Sci, Fuzhou, Fujian, Peoples R China
4.Fuzhou Univ, Fuzhou, Fujian, Peoples R China
5.Chinese Acad Sci, Qingdao Inst Biomass Energy & Bioproc Technol, Qingdao, Peoples R China
6.Fujian Normal Univ, Coll Life Sci, Fuzhou, Fujian, Peoples R China
7.Harvard Med Sch, Beth Israel Deaconess Med Ctr, Div Hemostasis & Thrombosis, Boston, MA USA
8.Huazhong Univ Sci &Technol, Tongji Med Coll, Sch Basic Med, Huazhong, Peoples R China

Recommended Citation:
Peng, Shuangzhou,Xue, Guangpu,Gong, Lihu,et al. A long-acting PAI-1 inhibitor reduces thrombus formation[J]. THROMBOSIS AND HAEMOSTASIS,2017,117(7):1338-1347.
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