Adrenomedullin inhibits angiotensin II-induced oxidative stress via Csk-mediated inhibition of Src activity

作者：Liu Jing; Shimosawa Tatsuo; Matsui Hiromitsu; Meng Fanyin; Supowit Scott C; DiPette Donald J; Ando Katsuyuki; Fujita Toshiro^*

来源：American Journal of Physiology - Heart and Circulatory Physiology, 2007, 292(4): H1714-H1721.

DOI：10.1152/ajpheart.00486.2006

• reactive oxygen species
• antioxidant
• lucigenin
• carboxy-termial Src kinase

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.

• 出版日期2007-4