Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Centre, Peking Union Medical College (PUMC), 5 Pan Jia Yuan Nan Li Chaoyang District, Beijing, 100021, People's Republic of China.
State Key Laboratory of Cardiovascular Disease, Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases, Diagnostic Laboratory Service, Center of Laboratory Medicine, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China.
Cardiovasc Drugs Ther. 2022 Feb;36(1):31-44. doi: 10.1007/s10557-020-07135-1. Epub 2021 Jan 11.
P-selectin glycoprotein ligand-1 (PSGL-1) acts as a crucial regulator for the inflammatory cells infiltration by mediating the adhesion of leukocytes. However, the role of PSGL-1 in aortic aneurysm remains elusive. Here, we investigated the role of PSGL-1 in aortic aneurysm (AA) development.
We first detected PSGL-1 expression in samples from aortic aneurysm patients and mouse AA models via western blotting, immunofluorescence, and flow cytometry, and then we used global PSGL-1 knockout mice and their wild type controls to establish an aortic aneurysm model induced by deoxycorticosterone acetate (DOCA) plus high salt (HS). The incidence, fatality rates, and the pathological changes of aortic aneurysm were analyzed in each group. The inflammation, adhesion molecules expression, and PSGL-1 mediated leukocyte-endothelial adhesion and their underlying mechanisms were explored further.
Increased PSGL-1 levels were observed in human and mouse aortic aneurysm, and on leukocytes of mice treated with DOCA+HS. PSGL-1 deficiency reduced the incidence and severity of aortic aneurysm significantly, as well as decreased elastin fragmentation, collagen accumulation, and smooth muscle cells degeneration. Mechanistically, the protective effect of PSGL-1 inhibition was mediated by the reduced adhesion molecules, and the subsequently reduced leukocyte-endothelial adhesion through the NF-κB pathway, which finally led to reduced inflammatory cells infiltration and decreased inflammatory factors expression.
PSGL-1 deficiency is protective against inflammatory cells migration and recruitment in the condition of AA through attenuation of leukocyte-endothelial adhesion. Inhibition of PSGL-1 may be a potential therapeutic target for the prevention and treatment of human AA.
P 选择素糖蛋白配体-1（PSGL-1）通过介导白细胞的黏附，作为炎症细胞浸润的关键调节剂。然而，PSGL-1 在主动脉瘤中的作用仍不清楚。在这里，我们研究了 PSGL-1 在主动脉瘤（AA）发展中的作用。
我们首先通过 Western blot、免疫荧光和流式细胞术检测了来自主动脉瘤患者和小鼠 AA 模型的 PSGL-1 表达，然后使用全局 PSGL-1 敲除小鼠及其野生型对照建立了由去氧皮质酮醋酸盐（DOCA）加高盐（HS）诱导的主动脉瘤模型。分析了每组的发病率、死亡率和主动脉瘤的病理变化。进一步探讨了炎症、黏附分子表达以及 PSGL-1 介导的白细胞-内皮黏附和它们的潜在机制。
在人类和小鼠的主动脉瘤以及接受 DOCA+HS 治疗的小鼠的白细胞中观察到 PSGL-1 水平升高。PSGL-1 缺失显著降低了主动脉瘤的发生率和严重程度，同时减少了弹性蛋白断裂、胶原积累和平滑肌细胞变性。机制上，PSGL-1 抑制的保护作用是通过减少黏附分子介导的，随后通过 NF-κB 通路减少白细胞-内皮黏附，最终导致炎症细胞浸润减少和炎症因子表达降低。
PSGL-1 缺失通过减弱白细胞-内皮黏附，在 AA 条件下对炎症细胞迁移和募集具有保护作用。抑制 PSGL-1 可能是预防和治疗人类 AA 的潜在治疗靶点。
