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

Authors: Liu, J  Shimosawa, T  Matsui, H  Meng, F  Supowit, SC  DiPette, DJ  Ando, K  Fujita, T 
Citation: Liu J, etal., Am J Physiol Heart Circ Physiol. 2007 Apr;292(4):H1714-21. Epub 2006 Oct 27.
Pubmed: (View Article at PubMed) PMID:17071733
DOI: Full-text: DOI:10.1152/ajpheart.00486.2006

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.

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CRRD Object Information
CRRD ID: 5134364
Created: 2011-07-01
Species: All species
Last Modified: 2011-07-01
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.