Alleviation of A disintegrin and metalloprotease 10 (ADAM10) on thromboangiitis obliterans involves the HMGB1/RAGE/NF-κB pathway
Alleviation of A disintegrin and metalloprotease 10 (ADAM10) on thromboangiitis obliterans involves the HMGB1/RAGE/NF-κB pathway
复制标题
A 解整合素和金属蛋白酶 10 (ADAM10) 对血栓闭塞性脉管炎的缓解涉及 HMGB1/RAGE/ NF-κB 通路
DOI：
10.1016/j.bbrc.2018.09.002
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发表时间：
2018-10-20
影响因子：
3.1
通讯作者：
Yuan, Hai
中科院分区：
文献类型：
--
作者：
Liu, Cheng;Kong, Xiangqian;Yuan, Hai
血栓闭塞性脉管炎(TAO)，又称Buerger病，是一种影响肢体中小型血管的非动脉粥样硬化性炎症性疾病。然而，TAO背后的机制仍不清楚。A去整合素和金属蛋白酶10(ADAM10)作为一种炎症介质，被认为在TAO的发生发展中起抑制作用。因此，本研究的目的是研究ADAM10在月桂酸钠诱导的TAO大鼠模型中的作用并阐明其可能的机制。雄性Wistar大鼠随机分为假手术组(Sham)、TAO模型组(TAO)、ADAM10低剂量注射组(ADAM10-LD)和高剂量注射组(ADAM10-HD)，每组6只。治疗14天后，彩色多普勒超声和血液学分析显示，TAO大鼠的全血粘度和血小板计数均高于假手术组。组织学评价和透射电子显微镜显示TAO大鼠血管内皮细胞和血管平滑肌超微结构损伤，表现为内质网断裂、细胞数量减少、纤颤等。另一方面，ADAM10可明显减轻TAO大鼠的典型体征和症状，并呈剂量依赖关系。实时定量聚合酶链式反应和免疫印迹结果显示，TAO大鼠高迁移率族蛋白B1(HMGB1)、晚期糖基化终产物受体(RAGE)和核因子-kappaB(NF-kappa B)的表达增加，而ADAM10处理组大鼠高迁移率族蛋白1(HMGB1)和核因子-kappaB的表达均降低。综上所述，这些结果提示ADAM10通过RAGE/NF-kappa B信号通路减轻月桂酸钠诱导的大鼠TAO的症状，并为TAO的分子基础和潜在的治疗策略提供了洞察力。(C)2018年由Elsevier Inc.出版。
Thromboangiitis obliterans (TAO), also known as Buerger's disease, is a nonatherosclerotic inflammatory disease that influences medium- and small-sized blood vessels of extremities. However, mechanisms underlying TAO are still unclear. As a mediator associated with inflammation, A disintegrin and metalloprotease 10 (ADAM10) was hypothesized to play inhibitory roles in the development of TAO. Thus, the objective of this study is to investigate the effects of ADAM10 in a sodium laurate-induced TAO rat model and elucidate underlying mechanisms. Male Wistar rats were randomly divided into four groups (n = 6) for treatment: sham-operated (SHAM), TAO model (TAO), ADAM10 low dose injection (3 mg/kg; ADAM10-LD) and ADAM10 high dose injection (6 mg/kg; ADAM10-HD). After 14-day treatment, color Doppler ultrasound and hematology analysis indicated TAO rats displayed higher whole blood viscosity and blood platelet count compared with those in the SHAM group. Histologic evaluation and transmission electron microscopy revealed that the ultrastructural damages of vascular smooth muscle and endothelial cells were observed in TAO rats, such as fractured endoplasmic reticulum, decreased cell counts, and fibrillation. On the other hand, the typical signs and symptoms of TAO rats were significantly alleviated via ADAM10 treatment with a dose-dependent pattern. Real-time PCR and western blot results revealed that the expression of high-mobility-group box 1 (HMGB1), receptor for advanced glycation end-products (RAGE) and nuclear factor-kappa B (NF-kappa B) increased in TAO rats whereas decreased by ADAM10 treatment in both mRNA and protein levels. In conclusion, the results suggest ADAM10 alleviates symptoms of sodium laurate-induced TAO in rats via the RAGE/NF-kappa B signaling pathway and provides insight into the molecular basis and a potential therapeutic strategy for TAO. (C) 2018 Published by Elsevier Inc.