title: Adenosine A2A receptor signaling regulation of cardiac NADPH oxidase activity.
abstract: Cardiac tissues express constitutively an NADPH oxidase, which generates reactive oxygen species (ROS) and is involved in redox signaling. Myocardial metabolism generates abundant adenosine, which binds to its receptors and plays important roles in cardiac function. The adenosine A2A receptor (A2AR) has been found to be expressed in cardiac myocytes and coronary endothelial cells. However, the role of the A2AR in the regulation of cardiac ROS production remains unknown. We found that knockout of A2AR significantly decreased (39+/-8%) NADPH-dependent O2- production in mouse hearts compared to age (10 weeks)-matched wild-type controls. This was accompanied by a significant decrease in Nox2 (a catalytic subunit of NADPH oxidase) protein expression, and down-regulation of ERK1/2, p38MAPK, and JNK phosphorylation (all P<0.05). In wild-type mice, intraperitoneal injection of the selective A2AR antagonist SCH58261 (3-10 mg/kg body weight for 90 min) inhibited phosphorylation of p47phox (a regulatory subunit of Nox2), which was accompanied by a down-regulated cardiac ROS production (48+/-8%), and decreased JNK and ERK1/2 activation by 54+/-28% (all P<0.05). In conclusion, A2AR through MAPK signaling regulates p47phox phosphorylation and cardiac ROS production by NADPH oxidase. Modulation of A2AR activity may have potential therapeutic applications in controlling ROS production by NADPH oxidase in the heart.
authors.affiliation: Cardiovascular Research, Division of Biochemical Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK.
authors.forename: David
authors.initials: D
authors.lastname: Ribé
authors.forename: David
authors.initials: D
authors.lastname: Sawbridge
authors.forename: Sapna
authors.initials: S
authors.lastname: Thakur
authors.forename: Martin
authors.initials: M
authors.lastname: Hussey
authors.forename: Catherine
authors.initials: C
authors.lastname: Ledent
authors.forename: Ian
authors.initials: I
authors.lastname: Kitchen
authors.forename: Susanna
authors.initials: S
authors.lastname: Hourani
authors.forename: Jian-Mei
authors.initials: JM
authors.lastname: Li
mesh_terms: D000241:Adenosine / Q000378:metabolism; D000818:Animals; D015971:Gene Expression Regulation, Enzymologic; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism*; D010766:Phosphorylation; D017382:Reactive Oxygen Species; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D017382:Reactive Oxygen Species; D043705:Receptor, Adenosine A2A; D019255:NADPH Oxidases; D000241:Adenosine