Abstract
Neurodegenerative disorders and brain damage are initiated by excessive production of reactive oxygen species (ROS), which leads to tissue injury, cellular death and inflammation. In cellular anti-oxidant systems, heme oxygenase-1 (HO-1) is an oxidative-sensor protein induced by ROS generation or carbon monoxide (CO) release. CO releasing molecules (CORMs), including CORM-3, exert anti-oxidant and anti-inflammatory effects. However, the molecular mechanisms of CORM-3-induced HO-1 expression and protection against interleukin (IL)-1β-induced inflammatory responses have not been fully elucidated in rat brain astrocytes (RBA-1). To study the regulation of CORM-3-induced HO-1 expression, signaling pathways, promoter activity, mRNA and protein expression were assessed following treatment with pharmacological inhibitors and gene-specific siRNA knockdown. We found that CORM-3 mediated HO-1 induction via transcritional and translational processes. Furthermore, CORM-3-induced HO-1 expression was mediated by phosphorylation of several protein kinases, such as c-Src, Pyk2, protein kinase Cα (PKCα) and p42/p44 mitogen-activated protein kinase (MAPK), which were inhibited by respective pharmacological inhibitors or by gene-specific knockdown with siRNA transfections. Next, we found that CORM-3 sequentially activated the c-Src/Pyk2/PKCα/p42/p44 MAPK pathway, thereby up-regulating mRNA for the activator protein (AP)-1 components c-Jun and c-Fos; these effects were attenuated by an AP-1 inhibitor (Tanshinone IIA; TSIIA) and other relevant inhibitors. Moreover, CORM-3-induced upregulation of HO-1 attenuated the IL-1β-induced cell migration and matrix metallopeptidase-9 mRNA expression in RBA-1 cells. These effects were reversed by an matrix metalloproteinase (MMP)2/9 inhibitor or by transfection with HO-1 siRNA.
Highlights
Cellular and tissue injuries initiate inflammatory responses to eliminate detrimental factors and injured tissues, thereby facilitating tissue repair
Increasing concentrations of CO releasing molecules (CORMs)-3 produced greater heme oxygenase-1 (HO-1) protein upregulation. These findings demonstrate that CORM-3-induced HO-1 expression is dependent on the concentration of CORM-3, as well as on treatment duration
We found that CORM-3 time-dependently induced HO-1 mRNA expression and promoter activity (Figures 1B,C)
Summary
Cellular and tissue injuries initiate inflammatory responses to eliminate detrimental factors and injured tissues, thereby facilitating tissue repair When this process is disturbed, the uncontrolled response produces excessive cell damage that results in tissue dysfunction or chronic inflammation. Several studies of neuronal degeneration indicate that chronic imbalance of redox states and inflammation are major contributors to brain damage (Dröge, 2002; von Bernhardi and Eugenín, 2012). These findings suggest that reactive oxygen species (ROS) are both cell defense molecules and critical regulators of cellular functions including proliferation, differentiation and apoptosis. Pharmacological interventions have been developed as protective and therapeutic strategies against oxidative stress-induced inflammation and neurodegeneration (Chong et al, 2005; Asaithambi et al, 2011)
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