Drug Design, Development and Therapy (Aug 2020)
Atorvastatin Combined with Low-Dose Dexamethasone Treatment Protects Endothelial Function Impaired by Chronic Subdural Hematoma via the Transcription Factor KLF-2
Abstract
Yueshan Fan,1– 3,* Dong Wang1,2 ,* Chenxu Rao,1– 3,* Ying Li,1,2 Hongtao Rong,1,2 Zengguang Wang,1,2 Jianning Zhang1,2 1Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, People’s Republic of China; 2Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin 300052, People’s Republic of China; 3Graduate School, Tianjin Medical University, Tianjin, 300000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianning Zhang; Zengguang Wang Tel +86 22-60817448Email [email protected]; [email protected]: 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.Keywords: chronic subdural hematoma, atorvastatin combined with low-dose dexamethasone treatment, endothelial inflammation and permeability, Kruppel-like factor 2
