单位：[1]Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China华中科技大学同济医学院附属同济医院器官移植研究所器官移植[2]The Key Laboratory of Chemistry for Natural Products, Guizhou Province and Chinese Academy of Sciences, Guiyang, China[3]State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, China[4]Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China[5]Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, China[6]Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
Background Both the complement and the coagulation systems play important roles in the development of hyperacute or acute antibody-mediated xenograft rejection. Atrase B is a novel metalloproteinase isolated from the venom ofNaja atra. In this study, we investigated the inhibitory effects of atrase B on complement activation and coagulation, as well as the effect on xenograft survival in a discordant xenotransplantation model. Methods The in vitro anti-complement activity of atrase B was evaluated using a normal human serum (NHS)-mediated complement-dependent cytotoxicity model with an immortalized porcine aortic endothelial cell line (iPEC) as the target. The in vivo inhibitory effects on complement activity and coagulation function were measured in rats after the administration of atrase B. Guinea pig hearts were transplanted heterotopically into Wistar rats with or without atrase B pre-treatment. Results Pre-treatment of the NHS with atrase B inhibited the cell lysis of iPECs in a dose-dependent manner. FACS analysis showed that atrase B potently suppressed the deposition of C5b-9, but not C3c and C4c, on iPECs. In vivo, atrase B-treated rats showed a significant reduction in serum complement activity; markedly prolonged PT, APTT, and TT; and a decreased plasma level of fibrinogen. When compared to PBS treatment evaluated at study endpoint, atrase B treatment significantly delayed xenograft rejection and attenuated pathologic damage, the formation of platelet microthrombi, and the deposition of fibrin and C5b-9. Conclusions The dual activities of anti-complement and anti-coagulation make atrase B a potential adjuvant therapeutic drug for use in xenotransplantation.
基金：
Guizhou Provincial Science and Technology Foundation [QKHRC[2016] 4018, QKHPTRC[2016]5625, QKHPTRC[2019]5702, QKHZC[2018]2828]; Major Scientific and Technological Project of Hainan province [ZDKJ2019009]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [U1812403]
第一作者单位：[1]Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
通讯作者：
通讯机构：[1]Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
推荐引用方式(GB/T 7714)：
fu cheng,shi lei,huang xia,et al.Atrase B, a novel metalloprotease with anti-complement and anti-coagulant activity, significantly delays discordant cardiac xenograft rejection[J].XENOTRANSPLANTATION.2020,27(5):doi:10.1111/xen.12616.
APA：
fu,cheng,shi,lei,huang,xia,feng,hao,tan,xiaosheng...&chen,gang.(2020).Atrase B, a novel metalloprotease with anti-complement and anti-coagulant activity, significantly delays discordant cardiac xenograft rejection.XENOTRANSPLANTATION,27,(5)
MLA：
fu,cheng,et al."Atrase B, a novel metalloprotease with anti-complement and anti-coagulant activity, significantly delays discordant cardiac xenograft rejection".XENOTRANSPLANTATION 27..5(2020)
