Adenosine A2A receptor signaling regulation of cardiac NADPH oxidase activity.
Adenosine A2A receptor signaling regulation of cardiac NADPH oxidase activity.
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DOI：
10.1016/j.freeradbiomed.2007.12.035
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发表时间：
2008-04-01
影响因子：
7.4
通讯作者：
Li, Jian-Mei
中科院分区：
文献类型：
--
作者：
Ribe, David;Sawbridge, David;Thakur, Sapna;Hussey, Martin;Ledent, Catherine;Kitchen, Ian;Hourani, Susanna;Li, Jian-Mei
心脏组织组成性表达NADPH氧化酶，产生活性氧（ROS）并参与氧化还原信号传导。心肌代谢产生丰富的腺苷，腺苷与其受体结合，在心功能中起重要作用。腺苷A2A受体（A2AR）被发现在心肌细胞和冠状动脉内皮细胞中表达。然而，A2AR在调节心脏ROS产生中的作用尚不清楚。我们发现，与年龄（10周）匹配的野生型对照相比，敲除A2AR显著降低（39±8%）小鼠心脏中nadph依赖性O2•−的产生。Nox2 （NADPH氧化酶的催化亚基）蛋白表达显著降低，ERK1/2、p38MAPK和JNK磷酸化下调（均P<0.05）。在野生型小鼠中，腹腔注射选择性A2AR拮抗剂SCH58261 （3-10 mg/kg体重，持续90分钟）可抑制p47phox （Nox2的调节亚基）磷酸化，同时心脏ROS生成下调（48±8%），JNK和ERK1/2激活降低54±28%（均P<0.05）。综上所述，A2AR通过MAPK信号调节p47phox磷酸化和NADPH氧化酶产生心脏ROS。A2AR活性的调节可能在控制心脏NADPH氧化酶产生ROS方面具有潜在的治疗应用。
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.
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