整合素α9β1和VCAM-1之间的相互作用促进中性粒细胞过活化,并介于中风后的严重心血管损伤.
Nilesh Pandey1, Harpreet Kaur1, Mehul R Chorawala2
1Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA.
Blood advances
|March 18, 2024
概括
脑卒中增加了深静脉血栓症 (DVT) 的风险. 中性粒细胞整合素α9和VCAM-1通过增强中性粒细胞粘附和过度激活来促进中风后的DVT. 马西坦抑制了这种途径,减少了DVT的严重程度.
科学领域:
- 心血管生物学 心血管生物学
- 血液学 血液学 血液学
- 免疫学 免疫学 免疫学
背景情况:
- 静脉血栓栓塞事件,特别是深静脉血栓症 (DVT),是中风后的主要并发症.
- 中性粒细胞在中风的早期反应中发挥着关键作用,并与DVT病变发生有关.
- 中性粒细胞上的整体素α9调节了在激活的内皮上对血管细胞粘附分子1 (VCAM-1) 的粘附.
研究的目的:
- 为了研究中性粒细胞整合素α9在中风后心脏病深血栓的发展中的作用.
- 阐明整合素α9对中风后DVT有所贡献的分子机制.
- 确定预防或治疗中风后DVT的潜在治疗点.
主要方法:
- 在人类和小鼠中风模型中测量中性粒细胞整合素α9和血VCAM-1水平.
- 在发生栓塞性中风后,对中性粒细胞特异性整体蛋白α9缺乏的小鼠和野生类型的 littermates 进行DVT严重程度的评估.
- 转录组分析以确定由α9/VCAM-1相互作用调节的途径.
- 关于中性粒细胞粘附,激活和内皮细胞亡的机制研究.
- 在体外查和验证macitentan作为α9/VCAM-1相互作用的抑制剂.
主要成果:
- 在中风患者和小鼠中观察到中性粒细胞整合素α9和血VCAM-1的升高.
- 中性粒细胞特异性整合素α9缺乏症显著降低了DVT的严重程度,中性粒细胞透和素化组合素H3在血栓中.
- α9/VCAM-1相互作用与中性粒细胞炎症,外细胞分裂,NF-κB信号传递和化学反应的途径有关.
- 综合素α9/VCAM-1信号促进了中性粒细胞的粘附,过活化,ERK酸化和内皮细胞的亡.
- 马西坦有效抑制了α9/VCAM-1相互作用和中性粒细胞粘附,在对照小鼠中降低了DVT的严重程度,但在α9缺乏的小鼠中却没有.
结论:
- 中性粒细胞整合蛋白α9是中风后DVT发展的关键调解者.
- α9/VCAM-1轴促进中性粒细胞的过度活化和粘附,有助于中风后严重心血管梗塞.
- 马西坦通过向α9/VCAM-1通路,成为中风后DVT的潜在治疗剂.
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