Propofol attenuates TNF-α-induced MMP-9 expression in human cerebral microvascular endothelial cells by inhibiting Ca^2+/CAMKⅡ/ERK/NF-kB signaling pathway  

作　　者：Xiao-wei Ding Xia Sun Xue-fang Shen Yan Lu Jia-qiang Wang Zhi-rong Sun Chang-hong Miao Jia-wei Chen 

机构地区：[1]Department of Anesthesiology,Fudan University Shanghai Cancer Center,Department of Oncology,Shanghai Medical College,Fudan University,Shanghai 200032,China [2]Shanghai Ninth People's Hospital,Shanghai JiaoTong University School of Medicine,Shanghai 200032,China

出　　处：《Acta Pharmacologica Sinica》2019年第10期1303-1313,共11页中国药理学报（英文版）

摘　　要：Metalloproteinase 9(MMP-9)is able to degrade collagen Ⅳ,an important component of blood-brain barrier(BBB).Expression of MMPs,especially MMP-9,correlates with BBB disruption during central nervous system inflammation.Propofol has been reported to have anti-inflammation effects.In this study,we investigated the effects of propofol on TNF-α-induced MMP-9 expression in human cerebral microvascular endothelial cells(hCMEC/D3 cells)and explored the underlying mechanisms.The hCMEC/D3 cells were treated with propofol(25 pM),followed by TNF-a(25 ng/mL).We showed that TNF-a treatment markedly increased MMP-9 expression and decreased collagen Ⅳ expression in hCMEC/D3 cells,which was blocked by pretreatment with propofol.TNF-ainduced downregulation of collagen Ⅳ was also reversed by MMP-9 knockdown with siRNA.We revealed that TNF-αupregulated MMP-9 expression in hCMEC/D3 cells through activation of Ca^2+/CAMK Ⅱ/ERK/NF-kB signaling pathway;co-treatment with inhibitors of CaMK Ⅱ(KN93),ERK(LY3214996),NF-kB(PDTC)or Ca^2+chelator(BAPTA-AM)abrogated the effect of TNF-αon MMP-9 expression.We further established an in vitro BBB model by co-culturing of hCMEC/D3 cells and human astrocytes for 6 days and measuring frans-endothelial electrical resistance(TEER)to reflect the BBB permeability.TNF-αtreatment markedly decreased TEER value,which was attenuated by pretreatment with propofol(25 mM)or MMP-9 knockdown with siRNA.In conclusion,propofol inhibits TNF-a-induced MMP-9 expression in hCMEC/D3 cells via repressing the Ca^2+/CAMK Ⅱ/ERK/NF-kB signaling pathway.TNF-aimpaired BBB integrity could be reversed by propofol,and propofol attenuates the inhibitory effect of TNF-a on collagen Ⅳ.

关 键 词：blood-brain barrier PROPOFOL TNF-A MMP-9 hCMEC/D3 cells 

分 类 号：R73[医药卫生—肿瘤]