Oxidative Stress Increases A₁Adenosine Receptor Expression by Activating Nuclear Factor κB

Abstract

The A1 adenosine receptor (A1AR) contributes to the cytoprotective action of adenosine under conditions known to generate reactive oxygen species (ROS). Pharmacological manipulation of A1AR expression has been shown to modulate this cytoprotective role. In this study, we provide evidence that ROS generated could increase the expression of the A1AR and thereby offset the detrimental effects of ROS. Incubation of DDT1MF-2 smooth muscle cells with ROS-generating chemotherapeutic agents, such as cisplatin (2.5 microM) or H2O2 (10 microM), elicited an increase in A1AR expression within 24 hr. The induction by H2O2 was reduced by the ROS scavenger catalase but not superoxide dismutase. Inhibition of nuclear factor kappa B (NF kappa B) by pyrrolidine dithiocarbamate (200 microM), dexamethasone (100 nM), or genistein (1 microM) abrogated the cisplatin-mediated increase in A1AR. Cisplatin promoted rapid translocation of NF kappa B (but not AP-1) to the nucleus, as detected by electrophoretic mobility shift assays and by Western blotting. A putative NF kappa B sequence in the A1AR promoter effectively competed with labeled kappa B probe for binding in nuclear preparations derived from DDT1MF-2 cells. Transient transfection of DDT1MF-2 cells with the A1AR promoter coupled to firefly luciferase reporter gene led to cisplatin-inducible and pyrrolidine dithiocarbamate-sensitive luciferase activity, suggesting the presence of functional NF kappa B binding site(s) in the A1AR promoter sequence. Treatment of cells with (R)-phenylisopropyladenosine (1 microM), an agonist of the A1AR, reduced cisplatin-mediated lipid peroxidation, which was reversed after blockade of the A1AR. These data suggest that ROS can increase the expression of the A1AR by activating NF kappa B regulatory site(s) on this gene and thereby enhance the cytoprotective role of adenosine.

Modulation of Adenosine Receptors by [60]Fullerene Hydrosoluble Derivative in SK-N-MC Cells

“…Thus, reactive oxygen species (ROS) can increase the expression of the A 1 receptor by activating NF kappa B regulatory site(s) on this gene and thereby enhance the cytoprotective role of adenosine. 42 Interestingly, the protective effect elicited by the hydrophilic fullerene derivative C 60 (C(COOH) 2 ) 2 against H 2 O 2 toxicity in cerebral microvessel endothelial cells (CMECs) seems to be mediated by a decreased phosphorylation of JNK and inhibition of ROS production. Consequently, C 60 (C(COOH) 2 ) 2 treatment could regulate several downstream signaling events, including reduced activation of transcription factor c-Jun and caspase-3 and inhibition of PARP cleavage and mitochondrial cytochrome c release.…”

Adenosine A1Receptor Protects Against Cisplatin Ototoxicity by Suppressing the NOX3/STAT1 Inflammatory Pathway in the Cochlea

“…Cisplatin-derived ROS increased the expression of the A 1 AR by activating NF-B (Nie et al, 1998), which could serve as a compensatory mechanism to reduce the toxicity of cisplatin. Other studies support a role of the ROS/NF-B axis in the regulation of the A 1 AR by oxidative stress (Pingle et al, 2004;Jajoo et al, 2006;Basheer et al, 2007;Pingle et al, 2007).…”

“…Accordingly, by acting on the A 1 AR, adenosine could serve as an endogenous inhibitor of NOX3 activity and expression. Interestingly, ROS positively regulates the expression of A 1 AR (Nie et al, 1998). To confirm that ROS could induce NOX3 expression, we exposed UB/OC-1 cells to H 2 O 2 and measured the expression of NOX3 by real-time PCR.…”

Adenosine suppresses activation of nuclear factor-κB selectively induced by tumor necrosis factor in different cell types

“…By using specific receptor anatagonists, we found that the effect of adenosine on TNF-induced NF-kB in myeloid cells is mediated through A 2 -type but not A 1 -type receptors. NF-kB activation induced by oxidative stress has been shown to induce the expression of A 1 adenosine receptor (Nie et al, 1998). Targeted deletion of the A3 adenosine receptor has been shown to induce resistance to myocardial ischemic injury (Guo et al, 2001) and stimulate inflammatory cells (Salvatore et al, 2000).…”