Propofol attenuates TNF-α-induced MMP-9 expression in human cerebral microvascular endothelial cells by inhibiting Ca2+/CAMK II/ERK/NF-κB signaling pathway.

Abstract

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 μM), followed by TNF-α (25 ng/mL). We showed that TNF-α treatment markedly increased MMP-9 expression and decreased collagen IV expression in hCMEC/D3 cells, which was blocked by pretreatment with propofol. TNF-α-induced downregulation of collagen IV was also reversed by MMP-9 knockdown with siRNA. We revealed that TNF-α upregulated MMP-9 expression in hCMEC/D3 cells through activation of Ca2+/CAMK II/ERK/NF-κB signaling pathway; co-treatment with inhibitors of CaMK II (KN93), ERK (LY3214996), NF-κB (PDTC) or Ca2+chelator (BAPTA-AM) abrogated the effect of TNF-α on 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 trans-endothelial electrical resistance (TEER) to reflect the BBB permeability. TNF-α treatment markedly decreased TEER value, which was attenuated by pretreatment with propofol (25 μM) or MMP-9 knockdown with siRNA. In conclusion, propofol inhibits TNF-α-induced MMP-9 expression in hCMEC/D3 cells via repressing the Ca2+/CAMKII/ERK/NF-κB signaling pathway. TNF-α-impaired BBB integrity could be reversed by propofol, and propofol attenuates the inhibitory effect of TNF-α on collagen IV.

• Authors: Xiao-Wei Ding, Xia Sun, Xue-Fang Shen, Yan Lu, Jia-Qiang Wang, Zhi-Rong Sun, Chang-Hong Miao, Jia-Wei Chen
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 40 Issue 10 Pg. 1303-1313 (Oct 2019) ISSN: 1745-7254 [Electronic] United States
• PMID: 31235816 (Publication Type: Journal Article)

Chemical References

• NF-kappa B
• Tumor Necrosis Factor-alpha
• Calcium-Calmodulin-Dependent Protein Kinase Type 2
• Matrix Metalloproteinase 9
• Calcium
• Propofol

Topics

• Calcium (metabolism)
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (antagonists & inhibitors, metabolism)
• Cells, Cultured
• Dose-Response Relationship, Drug
• Endothelial Cells (drug effects, metabolism)
• Humans
• MAP Kinase Signaling System (drug effects)
• Matrix Metalloproteinase 9 (genetics, metabolism)
• Microvessels (drug effects, metabolism)
• NF-kappa B (antagonists & inhibitors, metabolism)
• Propofol (pharmacology)
• Signal Transduction (drug effects)
• Structure-Activity Relationship
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, metabolism)