期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 44, 期 7, 页码 1433-1442出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2007.12.035
关键词
adenosine; receptor; free radicals; myocardium; NADPH oxidase
资金
- Biotechnology and Biological Sciences Research Council [BB/D009510/1] Funding Source: researchfish
- BBSRC [BB/D009510/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/D009510/1] Funding Source: Medline
- British Heart Foundation [PG/06/073/21118] Funding Source: Medline
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 A(2A) receptor (A(2A)R) 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 O-2(-) 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 p47(phox) (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 p47 (phox), 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. (c) 2008 Elsevier Inc. All rights reserved.
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