中国神经再生研究(英文版) ›› 2024, Vol. 19 ›› Issue (2): 434-439.doi: 10.4103/1673-5374.375345

• 原著:脊髓损伤修复保护与再生 • 上一篇    下一篇

阿加曲班可抑制损伤脊髓恢复的PAR1/JAK2/STAT3信号通路

  

  • 出版日期:2024-02-15 发布日期:2023-08-30
  • 基金资助:
    国家自然科学基金重点项目(81930070);国家自然科学基金项目(81972074);天津市自然科学基金重点项目(19JCZDJC34900)

Argatroban promotes recovery of spinal cord injury by inhibiting the PAR1/JAK2/STAT3 signaling pathway

Chenxi Zhao1, 2, #, Tiangang Zhou1, 2, #, Ming Li1, 2, #, †, Jie Liu1, 2, Xiaoqing Zhao3, Yilin Pang1, 2, Xinjie Liu1, 2, Jiawei Zhang1, 2, Lei Ma1, 2, Wenxiang Li3, Xue Yao1, 2, 3, *, Shiqing Feng1, 2, 3, *   

  1. 1Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China; 2International Science and Technology Cooperation Base of Spinal Cord Injury, Tianjin Key Laboratory of Spine and Spinal Cord Injury, Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China; 3Orthopedic Research Center of Shandong University, Cheeloo College of Medicine, Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, Shandong Province, China
  • Online:2024-02-15 Published:2023-08-30
  • Contact: Shiqing Feng, MD, PhD, sqfeng@tmu.edu.cn; Xue Yao, PhD, xueyao@tmu.edu.cn.
  • Supported by:
    This study was supported by the Key Project of the National Natural Science Foundation of China, No. 81930070 (to SF); the National Natural Science Foundation of China, No. 81972074 (to XY); and the Key Program of Natural Science Foundation of Tianjin, No. 19JCZDJC34900 (to XY).

摘要:

既往研究虽已表明人工合成的凝血酶抑制剂阿加曲班可减轻脑卒中后脑水肿,并减少神经元凋亡,但其是否也对脊髓损伤有修复作用,目前尚不清楚。实验以重物打击法建立T10中度脊髓损伤大鼠模型,而后持续3d腹腔注射阿加曲班进行治疗。结果显示,阿加曲班可有效促进脊髓损伤后神经功能的恢复,抑制脊髓损伤局部凝血酶的表达和活性。继而以生物信息学分析方法揭示发现差异基因主要富集于与脊髓损伤后星形胶质细胞增生和胶质瘢痕形成密切相关的JAK2/STAT3通路。最后以蛋白印迹以及免疫荧光染色法发现阿加曲班可下调脊髓损伤大鼠脊髓中蛋白酶激活受体1表达及其介导的PAR1/JAK2/STAT3信号通路,并抑制星形胶质细胞的活化和增殖,减少脊髓中的胶质瘢痕增生。因此阿加曲班可通过凝血酶介导的PAR1/JAK2/STAT3信号通路抑制星形胶质细胞增生,从而促进脊髓损伤后神经功能的恢复。

https://orcid.org/0000-0001-9437-7674 (Shiqing Feng); https://orcid.org/0000-0003-4904-9697 (Xue Yao).

关键词: 脊髓损伤, 阿加曲班, 凝血酶, 蛋白酶激活受体1, JAK, STAT, 星形胶质细胞, RNA测序, 丝氨酸蛋白酶, 波形蛋白

Abstract: Argatroban is a synthetic thrombin inhibitor approved by U.S. Food and Drug Administration for the treatment of thrombosis. However, whether it plays a role in the repair of spinal cord injury is unknown. In this study, we established a rat model of T10 moderate spinal cord injury using an NYU Impactor Moder III and performed intraperitoneal injection of argatroban for 3 consecutive days. Our results showed that argatroban effectively promoted neurological function recovery after spinal cord injury and decreased thrombin expression and activity in the local injured spinal cord. RNA sequencing transcriptomic analysis revealed that the differentially expressed genes in the argatroban-treated group were enriched in the JAK2/STAT3 pathway, which is involved in astrogliosis and glial scar formation. Western blotting and immunofluorescence results showed that argatroban downregulated the expression of the thrombin receptor PAR1 in the injured spinal cord and the JAK2/STAT3 signal pathway. Argatroban also inhibited the activation and proliferation of astrocytes and reduced glial scar formation in the spinal cord. Taken together, these findings suggest that argatroban may inhibit astrogliosis by inhibiting the thrombin-mediated PAR1/JAK2/STAT3 signal pathway, thereby promoting the recovery of neurological function after spinal cord injury.

Key words: argatroban, astrogliosis, JAK/STAT signaling pathway, protease-activated receptor-1, spinal cord injury, thrombin, vimentin