Blockade of Apoptosis Signal-Regulating Kinase 1 Attenuates Matrix Metalloproteinase 9 Activity in Brain Endothelial Cells and the Subsequent Apoptosis in Neurons after Ischemic Injury

Abstract

Conditions of increased oxidative stress including cerebral ischemia can lead to blood–brain barrier dysfunction via matrix metalloproteinase (MMP). It is known that MMP-9 in particular is released from brain endothelial cells is involved in the neuronal cell death that occurs after cerebral ischemia. In the intracellular signaling network, apoptosis signal-regulating kinase 1 (ASK1) is the main activator of the oxidative stress that is part of the pathogenesis of cerebral ischemia. ASK1 also promotes apoptotic cell death and brain infarction after ischemia and is associated with vascular permeability and the formation of brain edema. However, the relationship between ASK1 and MMP-9 after cerebral ischemia remains unknown. Therefore, the aim of the present study was to determine whether blocking ASK1 would affect MMP-9 activity in the ischemic brain and cultured brain endothelial cells. Our results showed that ASK1 inhibition efficiently reduced MMP-9 activity in vivo and in vitro. In endothelial cell cultures, ASK1 inhibition upregulated phosphatidylinositol 3-kinase/Akt/nuclear factor erythroid 2 [NF-E2]-related factor 2/heme oxygenase-1 signals and downregulated cyclooxygenase-2 signals after hypoxia/reperfusion. Additionally, in neuronal cell cultures, cell death occurred when neurons were incubated with endothelial cell-conditioned medium (EC-CM) obtained from the hypoxia/reperfusion group. However, after incubation with EC-CM and following treatment with the ASK1 inhibitor NQDI-1, neuronal cell death was efficiently decreased. We conclude that suppressing ASK1 decreases MMP-9 activity in brain endothelial cells, and leads to decreased neuronal cell death after ischemic injury.

Panax notoginseng saponins suppress lipopolysaccharide‐induced barrier disruption and monocyte adhesion on bEnd.3 cells via the opposite modulation of Nrf2 antioxidant and NF‐κB inflammatory pathways

“…As described above, the excessive generation of ROS or secretion of pro‐inflammatory cytokines may be the causes of TJs degradation and BBB disruption (Cheon et al, ; Da Fonseca et al, ). In this study, the protective effects of PNS on BBB integrity and TJs expression were also partially reversed by PI3K inhibition.…”

“…On the other hand, oxidative stress and inflammation also play crucial roles in BBB injury (Janyou et al, 2017;Zhang, Jiang, et al, 2017). Strong evidence indicates that excessive ROS generation may cause TJs degradation and BBB dysfunction, which lead to exogenous detrimental large molecules freely cross the barrier into the brain and further indirectly accelerate the progress of brain disorders (Cheon et al, 2016). Meanwhile, oversecretion of pro-inflammatory cytokines (e.g., IL-1β, TNF-α) may also disturb TJs expression and distribution in endothelial cells and increase BBB permeability (Da Fonseca et al, 2014).…”

“…Oxidative stress and inflammation are well‐known mechanisms accounting for BBB dysfunction (Janyou et al, ; Zhang et al, ). Excessive generation of reactive oxygen species (ROS) or pro‐inflammatory cytokines (e.g., IL‐1β and TNF‐α) probably result in TJs degradation and BBB disruption, which may further lead magnitude of xenobiotics to extravasate into brain parenchyma and aggravate the brain tissue damage (Cheon et al, ; Da Fonseca et al, ). Moreover, the recruitment of peripheral inflammatory cells due to the overexpression of adhesion molecules on cerebral endothelium is also involved in BBB injury (Lee, Lee, & Jung, ).…”

Integrated Omics Reveals Tollip as an Regulator and Therapeutic Target for Hepatic Ischemia‐Reperfusion Injury in Mice

“…For instance, GS‐459679, a small molecular inhibitor of ASK1, has been developed to rescue IR‐induced myocardium at the risk of death in mice . Furthermore, inhibiting ASK1 by its inhibitor NQD‐1 significantly protects against neuronal cell death after cerebral ischemia and exhibits potent inhibition of oxidative stress and cell death in renal IR injury . Therefore, we believe that blocking the Tollip‐ASK1 axis is translationally promising for hepatic IR injury.…”

Total Glycosides of Cistanche deserticola Promote Neurological Function Recovery by Inducing Neurovascular Regeneration via Nrf-2/Keap-1 Pathway in MCAO/R Rats

“…During I/R periods, excessive ROS is one of the main factors leading to the direct damage of brain neurons (Ding et al, 2014). ROS overproduction leads to the degradation of certain junctions and BBB disruption, which results in exogenous molecules entering into the brain through the BBB, leading to brain damage aggravation (Cheon et al, 2016;Zhang Q. Y. et al, 2017). Therefore, protection of the BBB by anti-oxidants has been regarded as a potential way to prevent reperfusion injury.…”