Gα12/13- and reactive oxygen species-dependent activation of c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinase by angiotensin receptor stimulation in rat neonatal cardiomyocytes
Gα12/13- and reactive oxygen species-dependent activation of c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinase by angiotensin receptor stimulation in rat neonatal cardiomyocytes
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DOI：
10.1074/jbc.m409710200
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发表时间：
2005-05-06
影响因子：
4.8
通讯作者：
Kurose, H
中科院分区：
文献类型：
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作者：
Nishida, M;Tanabe, S;Kurose, H
在本研究中，我们研究了活性氧（ROS）产生的信号转导机制以及ROS在血管紧张素II诱导的大鼠新生心肌细胞丝裂原激活蛋白激酶（MAPK）激活中的作用。在三种 MAPK 中，c-Jun NH2 末端激酶 (JNK) 和 p38 MAPK 需要 ROS 产生才能激活，而 NADPH 氧化酶抑制剂二亚苯基碘鎓会抑制激活。血管紧张素 II 诱导的 JNK 和 p38 MAPK 激活也受到 G α(12/13) 特异性 G 蛋白信号传导 (RGS) 结构域（一种 G α(12/13) 特异性抑制剂）表达的抑制，但不受 G α(q) 特异性 RGS 结构域的抑制。二亚苯基碘鎓抑制持续性活性 G α(12) 或 G α(13) 诱导的 JNK 和 p38 MAPK 激活，但不抑制细胞外信号调节激酶 (ERK)。血管紧张素 II 受体刺激迅速激活 G α(13)，而 G α(12/13) 特异性 RGS 结构域完全抑制该作用。此外，G α(12/13) 特异性而非 G α(q) 特异性 RGS 结构域抑制血管紧张素 II 诱导的 ROS 产生。显性负性 Rac 抑制血管紧张素 II 刺激的 ROS 产生、JNK 激活和 p38 MAPK 激活，但不影响 ERK 激活。 Rac 激活由 Rho 和 Rho 激酶介导，因为 Rac 激活受到 C3 毒素和 Rho 激酶抑制剂 Y27632 的抑制。此外，血管紧张素II诱导的Rho激活被Gα(12/13)特异性RGS结构域抑制，但不被显性负性Rac抑制。表皮生长因子受体激酶 AG1478 抑制剂不影响血管紧张素 II 诱导的 JNK 激活级联。这些结果表明，G α(12/13) 介导的通过 Rho 和 Rac 产生的 ROS 对于 JNK 和 p38 MAPK 激活至关重要。
In the present study, we examined signal transduction mechanism of reactive oxygen species (ROS) production and the role of ROS in angiotensin II-induced activation of mitogen-activated protein kinases (MAPKs) in rat neonatal cardiomyocytes. Among three MAPKs, c-Jun NH2-terminal kinase (JNK) and p38 MAPK required ROS production for activation, as an NADPH oxidase inhibitor, diphenyleneiodonium, inhibited the activation. The angiotensin II-induced activation of JNK and p38 MAPK was also inhibited by the expression of the G alpha(12/13)-specific regulator of G protein signaling (RGS) domain, a specific inhibitor of G alpha(12/13), but not by an RGS domain specific for G alpha(q). Constitutively active G alpha(12)- or G alpha(13)-induced activation of JNK and p38 MAPK, but not extracellular signal-regulated kinase (ERK), was inhibited by diphenyleneiodonium. Angiotensin II receptor stimulation rapidly activated G alpha(13), which was completely inhibited by the G alpha(12/13)-specific RGS domain. Furthermore, the G alpha(12/13)-specific but not the G alpha(q)-specific RGS domain inhibited angiotensin II-induced ROS production. Dominant negative Rac inhibited angiotensin II-stimulated ROS production, JNK activation, and p38 MAPK activation but did not affect ERK activation. Rac activation was mediated by Rho and Rho kinase, because Rac activation was inhibited by C3 toxin and a Rho kinase inhibitor, Y27632. Furthermore, angiotensin II-induced Rho activation was inhibited by G alpha(12/13)-specific RGS domain but not dominant negative Rac. An inhibitor of epidermal growth factor receptor kinase AG1478 did not affect angiotensin II-induced JNK activation cascade. These results suggest that G alpha(12/13)-mediated ROS production through Rho and Rac is essential for JNK and p38 MAPK activation.