NADPH oxidase 2-derived reactive oxygen species signal contributes to bradykinin-induced matrix metalloproteinase-9 expression and cell migration in brain astrocytes

In 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.These 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.Matrix metalloproteinases (MMPs) is a large family of zinc-dependent endopeptidases, which play an important role in the turnover of extracellular matrix (ECM) and pathophysiological processes [1]. In the central nervous system (CNS), MMPs, in particular MMP-9, have been shown to be involved in morphogenesis, wounding healing, and neurite outgrowth, [2]. Up-regulation of MMP-9 has been induced by various brain injuries, which may participate in the pathogenesis of brain diseases [3]. Moreover, cytokines and lipopolysaccharide (LPS) have been shown to induce MMP-9 expression and activity in culture rat brain astrocytes [4,5]. These studies demonstrated that MMP-9 may be involved in brain inflammation and injury.Reactive oxygen species (ROS) are produced by various enzymatic and chemical processes or directly inhaled, including O2-, ·OH, and hydrogen peroxide (H2O2). The ROS at low level have physiological roles as signaling molecules in various cellular and developmental processes [6,7] and killing of invading microorganisms [8]. In contrast, recent report indicated that oxidative stress plays an important role in the progression of various disea