Copyright © 2004, European Society of Cardiology
Adenosine produces nitric oxide and prevents mitochondrial oxidant damage in rat cardiomyocytes
aDepartment of Anesthesiology, CB#7010 University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7010, USA
bDepartment of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
cDepartment of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
dDepartment of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
* Corresponding author. Tel.: +1 919 843 4174; fax: +1 919 843 3805. Email address: zxu{at}aims.unc.edu
Objective: To examine if adenosine prevents oxidant-induced mitochondrial dysfunction by producing nitric oxide (NO) in cardiomyocytes.
Methods and results: Adenosine significantly enhanced the fluorescence of DAF-FM, a dye specific for NO, implying that adenosine induces synthesis of NO. Adenosine-induced NO production was blocked by both the nonspecific NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME) and N5-(1-Iminoethyl)-L-ornithine dihydrochloride (L-NIO), an inhibitor of endothelial NOS (eNOS), but not by N6-(1-Iminoethyl)-L-lysine hydrochloride (L-NIL), an inhibitor of inducible NOS (iNOS), indicating that adenosine activates eNOS. Adenosine also enhances eNOS phosphorylation and its activity. The adenosine A2 receptor antagonist 8-(3-chlorostyryl)caffeine but not the A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine prevented the increase in NO production. CGS21680, an adenosine A2 receptor agonist, markedly increased NO, further supporting the involvement of A2 receptors. Adenosine-induced NO production was blocked by 4-Amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo(3,4-d)pyrimidine (PP2), a selective Src tyrosine kinase inhibitor, suggesting that Src tyrosine kinase is crucial for adenosine-induced NO production. Adenosine-induced NO production was partially reversed by both wortmannin and Akt inhibitor indicating an involvement of PI3-kinase/Akt. Pretreatment of cells with adenosine prevented H2O2-induced depolarization of mitochondrial membrane potential (
m). The protective effect was blocked by L-NAME and L-NIO but not by L-NIL, indicating that eNOS plays a role in the action of adenosine. The protective effect of adenosine was further suppressed by KT5823, a specific inhibitor of protein kinase G (PKG), indicating the PKG may serve as a downstream target of adenosine.
Conclusion: Adenosine protects mitochondria from oxidant damage through a pathway involving A2 receptors, eNOS, NO, PI3-kinase/Akt, and Src tyrosine kinase.
KEYWORDS Adenosine; Nitric oxide; Mitochondria; Signal transduction
Time for primary review 16 days
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