Adrenomedullin inhibits angiotensin II-induced oxidative stress via Csk-mediated inhibition of Src activity.
Adrenomedullin inhibits angiotensin II-induced oxidative stress via Csk-mediated inhibition of Src activity.
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DOI：
10.1152/ajpheart.00486.2006
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发表时间：
2007-04
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影响因子：
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通讯作者：
Jing Liu;T. Shimosawa;Hiromitsu Matsui;F. Meng;S. Supowit;D. DiPette;K. Ando;T. Fujita
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文献类型：
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作者：
Jing Liu;T. Shimosawa;Hiromitsu Matsui;F. Meng;S. Supowit;D. DiPette;K. Ando;T. Fujita
我们已经证明，肾上腺髓质素(AM)通过减轻AM缺陷小鼠观察到的增加的氧化应激来保护血管紧张素II(Ang II)诱导的心血管损伤。然而，这种活动背后的机制(S)仍不清楚。为了解决这个问题，我们研究了AM对Ang II刺激的大鼠主动脉血管平滑肌细胞(VSMCs)产生活性氧(ROS)的影响。Ang II通过激活NADPH氧化酶显著增加ROS的产生。AM以浓度依赖的方式显著减弱这一效应。此作用可被二丁基-cAMP模拟，并被蛋白激酶A抑制剂N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide盐酸盐(H-)和AM/CGRP受体拮抗剂CGRP(8-37)阻断。AM的这种抑制作用也在结构性活性的Src表达后消失。此外，AM通过诱导COOH末端的Src激酶(CSK)的激活来阻断Ang II信号，进而抑制了Src的激活。这些数据首次证明AM通过激活CSK来减弱Ang II诱导的VSMCs内ROS的增加，从而抑制Src的活性。
We have demonstrated that adrenomedullin (AM) protects against angiotensin II (ANG II)-induced cardiovascular damage through the attenuation of increased oxidative stress observed in AM-deficient mice. However, the mechanism(s) that underlie this activity remain unclear. To address this question, we investigated the effect of AM on ANG II-stimulated reactive oxygen species (ROS) production in cultured rat aortic vascular smooth muscle cells (VSMCs). ANG II markedly increased ROS production through activation of NADPH oxidase. This effect was significantly attenuated by AM in a concentration-dependent manner. This effect was mimicked by dibutyl-cAMP and blocked by pretreatment with N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide hydrochloride (H-89), a protein kinase A inhibitor, and CGRP(8-37), an AM/CGRP receptor antagonist. This inhibitory effect of AM was also lost following the expression of a constitutively active Src. Moreover, AM intersected ANG II signaling by inducing COOH-terminal Src kinase (Csk) activation that, in turn, inhibits Src activation. These data, for the first time, demonstrate that AM attenuates the ANG II-induced increase in ROS in VSMCs via activation of Csk, thereby inhibiting Src activity.