Atorvastatin Combined with Low-Dose Dexamethasone Treatment Protects Endothelial Function Impaired by Chronic Subdural Hematoma via the Transcription Factor KLF-2

被引：15
作者：
Fan, Yueshan [1 ,2 ,3 ]
Wang, Dong [1 ,2 ]
Rao, Chenxu [1 ,2 ,3 ]
Li, Ying [1 ,2 ]
Rong, Hongtao [1 ,2 ]
Wang, Zengguang [1 ,2 ]
Zhang, Jianning [1 ,2 ]
机构：
[1] Tianjin Med Univ, Dept Neurosurg, Gen Hosp, Tianjin 300052, Peoples R China
[2] Minist Educ & Tianjin City, Key Lab Postneuroinjury Neurorepair & Regenerat C, Tianjin Neurol Inst, Tianjin 300052, Peoples R China
[3] Tianjin Med Univ, Grad Sch, Tianjin 300000, Peoples R China
来源：
DRUG DESIGN DEVELOPMENT AND THERAPY | 2020年 / 14卷
基金：
中国国家自然科学基金;
关键词：
chronic subdural hematoma; atorvastatin combined with low-dose dexamethasone treatment; endothelial inflammation and permeability; Kruppel-like factor 2; ANTITHROMBOTIC DRUG-USE; KRUPPEL-LIKE FACTOR-2; EXPRESSION;
D O I：
10.2147/DDDT.S256050
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
Objective: Our previous study showed that the combination therapy with atorvastatin and low-dose dexamethasone protected endothelial cell function in chronic subdural hematoma (CSDH) injury. In this study, we aimed to investigate the mechanism underlying the effects of this combination therapy on CSDH-induced cell dysfunction. Methods: Monocytes and endothelial cells were cocultured with CSDH patient hematoma samples to mimic the pathological microenvironment of CSDH. Monocytes (THP-1 cells) and endothelial cells (hCMEC/D3 cells) were cocultured in a transwell system for 24 h before stimulation with hematoma samples diluted in endothelial cell medium (ECM) at a 1:1 ratio. Tight junction markers were detected by Western blotting, PCR and immunofluorescence. hCMEC/D3 cells were collected for Western blot and PCR analyses to detect changes in the expression levels of vascular cell adhesion molecule (VCAM-1), intercellular adhesion molecule (ICAM-1), and Kruppel-like factor 2 (KLF-2). The IL-6, IL-10 and VEGF levels in the supernatant were measured by enzyme-linked immunosorbent assay (ELISA). Results: KLF-2 expression in endothelial cells was decreased after stimulation with CSDH patient hematoma samples, but combination therapy with atorvastatin and low-dose dexamethasone reversed this trend. KLF-2 protected injured cells by increasing the expression of VE-cadherin and ZO-1; attenuating the expression of VCAM-1, ICAM-1, IL-6 and VEGF; and enhancing the expression of IL-10, all of which play pivotal roles in endothelial inflammation. Moreover, the effect of combination therapy with atorvastatin and low-dose dexamethasone was obviously reduced in endothelial cells with KLF-2 knockdown compared with normal cells. Conclusion: Coculture with hematoma samples decreased KLF-2 expression in human cerebral endothelial cells. Combination therapy with atorvastatin and low-dose dexamethasone counteracted hematoma-induced KLF-2 suppression in human cerebral endothelial cells to attenuate robust endothelial inflammation and permeability. KLF-2 plays an important role in drug therapy for CSDH and may become the key factor in treatment and prognosis.
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收藏
页码：3291 / 3299
页数：9
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