Submitted on May 12, 2006
Accepted on September 21, 2006
Adrenomedullin Inhibits Angiotensin II-Induced Oxidative Stress
Via Csk-Mediated Inhibition of Src Activity
Jing Liu1, Tatsuo Shimosawa2, Hiromitsu Matsui1, Fanyin Meng3, Scott C Supowit4, Donald J DiPette4, Katsuyuki Ando1, and Toshiro Fujita1*
1 Department of Endocrinology and Nephrology, University of Tokyo, Tokyo, Japan
2 Department of Clinical Laboratory Medicine, University of Tokyo, Tokyo, Japan
3 Medicine, Texas A&M University, Temple, Texas, United States
4 Department of Medicine, Texas A&M University, Temple, Texas, United States
* To whom correspondence should be addressed. E-mail: fujita-dis{at}h.u-tokyo.ac.jp.
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 remains 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 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 expression of a constitutively active Src．Moreover, AM intersected Ang II signaling by inducing 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.
