Abstract
BackgroundMatrix metalloproteinase-9 (MMP-9) plays a crucial role in pathological processes of brain inflammation, injury, and neurodegeneration. Moreover, bradykinin (BK) induces the expression of several inflammatory proteins in brain astrocytes. Recent studies have suggested that increased oxidative stress is implicated in the brain inflammation and injury. However, whether BK induced MMP-9 expression mediated through oxidative stress remains virtually unknown. Herein we investigated the role of redox signals in BK-induced MMP-9 expression in rat brain astrocytes (RBA-1 cells).ResultsIn the study, we first demonstrated that reactive oxygen species (ROS) plays a crucial role in BK-induced MMP-9 expression in cultured brain astrocytes (in vitro) and animal brain tissue (in vivo) models. Next, BK-induced MMP-9 expression is mediated through a Ca2+-mediated PKC-α linking to p47phox/NADPH oxidase 2 (Nox2)/ROS signaling pathway. Nox2-dependent ROS generation led to activation and up-regulation of the downstream transcriptional factor AP-1 (i.e. c-Fos and c-Jun), which bound to MMP-9 promoter region, and thereby turned on transcription of MMP-9 gene. Functionally, BK-induced MMP-9 expression enhanced astrocytic migration.ConclusionsThese results demonstrated that in RBA-1 cells, activation of AP-1 (c-Fos/c-Jun) by the PKC-α-mediated Nox2/ROS signals is essential for up-regulation of MMP-9 and cell migration enhanced by BK.
Highlights
Matrix metalloproteinase-9 (MMP-9) plays a crucial role in pathological processes of brain inflammation, injury, and neurodegeneration
These results suggested that Reactive oxygen species (ROS) contribute to BK-induced Matrix metalloproteinases (MMPs)-9 expression via enhancing its gene transcriptional activity in Rat brain astrocytes (RBA-1) cells
These results suggested that BK stimulates Activator protein 1 (AP-1) (i.e. c-Fos and c-Jun) activation via the Protein kinase C-α (PKC-α)-dependent NADPH oxidase 2 (Nox2)/ROS generation, which is essential for up-regulation of MMP-9 in RBA-1 cells
Summary
Matrix metalloproteinase-9 (MMP-9) plays a crucial role in pathological processes of brain inflammation, injury, and neurodegeneration. We investigated the role of redox signals in BK-induced MMP-9 expression in rat brain astrocytes (RBA-1 cells). Many proinflammatory mediators like bradykinin (BK) induce expression of several inflammatory genes during brain injury by increasing ROS production [7,10]. Increasing evidence attributes the neurodegenerative diseases such as Alzheimer’s disease (AD) to oxidative stress (generation of free radicals) that leads to brain inflammation during CNS pathogenesis [7,10,11]. The effects of BK associated with ROS generation have been reported in several organ diseases [13], BK-induced ROS-mediated MMP-9 responses are not well characterized in rat brain astrocytes (RBA-1) cells
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