Reactive Oxygen Species-Dependent c-Fos/Activator Protein 1 Induction Upregulates Heme Oxygenase-1 Expression by Bradykinin in Brain Astrocytes

Abstract

Heme oxygenase-1 (HO-1) plays a crucial role in tissue pathological changes such as brain injuries. Our previous studies have demonstrated that bradykinin (BK) induces the expression of several inflammatory proteins, including matrix metalloproteinase-9 and COX-2, via mitogen-activated protein kinases and nuclear factor-κB (NF-κB) in rat brain astrocytes (RBA-1). However, the molecular mechanisms underlying BK-induced HO-1 expression in RBA-1 cells remain poorly defined. Here we demonstrated that BK induced HO-1 expression and enzymatic activity via a B(2) BK receptor-activated reactive oxygen species (ROS)-dependent signaling pathway. NADPH oxidase (Nox)-dependent ROS generation led to activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun-N-terminal kinase (JNK) and then activated the downstream molecules NF-κB and c-Jun, respectively. The c-Fos, an activator protein 1 (AP-1) subunit, was upregulated by activation of NF-κB and c-Jun, which bound to HO-1 promoter and thereby turned on transcription of HO-1 gene. The rat HO-1 promoter containing a putative AP-1 cis-binding site was identified as a crucial domain linking to BK action. Taken together, these results suggested that in RBA-1 cells, activation of ERK/NF-κB and JNK/c-Jun cascades by a Nox/ROS-dependent event enhancing c-Fos/AP-1 activity is essential for HO-1 upregulation and activation induced by BK. Moreover, ROS-dependent NF-E2-related factor 2 activation also contributes to HO-1 induction by BK in astrocytes.

Cerebroprotection of flavanol (-)-epicatechin after traumatic brain injury via Nrf2-dependent and -independent pathways

“…Because EC treatment reduced HO-1 protein expression, we speculate that EC might activate an Nrf2-independent pathway that modulates HO-1 expression and iron deposition in the CCI model. This finding is in line with previous studies which showed that activator protein 1 (AP-1) regulates HO-1 gene expression in Nrf2-deficient fibroblasts [56] and normal brain astrocytes [57]. AP-1 is a stress-activated transcription factor and has been regarded as an inflammatory signaling molecule after TBI [58].…”

Arsenic modulates heme oxygenase-1, interleukin-6, and vascular endothelial growth factor expression in endothelial cells: roles of ROS, NF-κB, and MAPK pathways

“…Although NF-jB has been shown to be induced by stimuli that also up-regulate HO-1, its role in HO-1 gene expression is unclear in the literature. More than one study suggests a direct relationship between NF-jB activation and HO-1 induction (Hsieh et al 2010;Juan et al 2005); however, others show HO-1 expression is negatively controlled by NF-jB activity (Hartsfield et al 1998;Rushworth et al 2010). Our data demonstrate that NF-jB appears to be directly involved in HO-1 gene expression in response to arsenic in SVEC4-10 cells, because treatment of cells with Bay11-7082 (IjB-a phosphorylation inhibitor) significantly attenuates the induction.…”

A time course of NADPH-oxidase up-regulation and endothelial nitric oxide synthase activation in the hippocampus following neurotrauma

“…Mechanistically, NOX activation is associated with increased intracellular Ca 2+ [46,47], protein kinase C (PKC) functions [81-83] and participates in the cell signaling processes. NOX derived O 2 .− contributes to the expression of matrix metalloproteinase-9 (MMP-9) and the activation of extracellular signal-regulated kinase (ERK) [81,82], c-Jun-N-terminal kinase (JNK) and nuclear factor kappa-B (NF-kB) [82-84]. Consequently, NOX up-regulation has been implicated in microglia activation/proliferation [21,63,85], inflammation [39,40,86,87] and mediated apoptotic neuronal death [44,45,88].…”