Adenosine A2A receptor antagonist (SCH 58261) attenuates AngII-induced ROS production and preserved endothelial function in mouse aortas

Junjie Du, Susanna Hourani, Jian-Mei Li. Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey GU2 7XH, United Kingdom.

The endothelium expresses abundantly an adenosine A2A receptor (A2AR) which plays important roles in the regulation of vascular function. The endothelium expresses also an NADPH oxidase which by generating reactive oxygen species (ROS) participates in normal endothelial redox-signalling, and is involved in the pathogenesis of endothelial dysfunction. However little is known about the role of A2AR in AngII-induced endothelial ROS production. In this study, we investigated the effect of A2AR blockade on AngII-induced ROS production and endothelium function using freshly isolated aortas from CD1 mice at 10-12 weeks of age. Comparison between 2 groups was made using student t-test. Significance was accepted at P < 0.05. All data are presented as mean ± SEM. Compared to vessels treated with vehicle, acute AngII (200 nM for 45 min) treatment significantly increased the ROS production in the vessel wall as detected by DHE (Fluorescence intensity: 28±1.3 vs 55±4.2). These AngII effects were inhibited back to the control levels in the presence of a specific A2AR antagonist, SCH58261 (100 nM). Compared to control vessels, treatment with AngII severely compromised the endothelium-dependent vessel relaxation to acetylcholine as assessed by an organ bath (Emax: 89±2.5% vs 71±3.2%). Addition of SCH58261 (100 nM) or tiron (20 mM, a specific cell membrane permeable superoxide scavenger) during AngII stimulation protected the endothelium from AngII damage and preserved endothelium-dependent vessel relaxation to acetylcholine (Emax: 88±3.0%). The endothelium-dependence of the relaxation to acetylcholine was confirmed by mechanical denudation of the endothelium. In conclusion, blockade of A2AR protects the endothelium from acute AngII-induced oxidative stress and endothelium dysfunction. A2AR antagonist may have a potential therapeutic application in treating endothelial oxidative stress-related diseases.