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Submitted on November 21, 2003
Accepted on April 1, 2004
Department of Clinical and Molecular Endocrinology; Tokyo Medical and Dental University Graduate School, Tokyo 113-8519, Japan
* To whom correspondence should be addressed. E-mail: tyoshimoto.cme{at}tmd.ac.jp.
Recent adrenomedullin (AM) gene-targeting studies have proposed a novel concept that AM plays a protective role against oxidative stress in vivo. The present study was undertaken to explore the underlying molecular mechanism of the putative anti-oxidant action of AM against angiotensin II (Ang II)-induced reactive oxygen species (ROS) generation in rat aortic smooth muscle cells (VSMCs). Intracellular ROS levels were measured by DCF fluorescence. Redox-sensitive c-Jun amino-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK)1/2 activation and gene expression induced by Ang II in VSMCs were also studied. AM dose-relatedly (10-8
10-7M) inhibited Intracellular ROS generation stimulated by Ang II (10-7M), as mimicked by dibutyl-cAMP, whose effect was inhibited by the pretreatment with H-89, a protein kinase A inhibitor, and CGRP(8-37), an AM/CGRP receptor antagonist. Ang II induced JNK and ERK1/2 activation via a redox-sensitive manner, whereas AM inhibited JNK, but not ERK1/2 activation by Ang II. Furthermore, AM inhibited Ang II-induced redox-sensitive gene expression (PAI-1, MCP-1) in the same manner as did N-acetyl cysteine (NAC), a potent antioxidant. AM also inhibited Ang II-induced up-regulation of Nox1, a critical membrane-bound component of NADPH oxidase in VSMCs, in the same degree as NAC. Taken together, our study demonstrates for the first time that AM directly inhibits intracellular ROS generation via AM receptor-mediated and c-AMP-PKA-dependent mechanism in VSMCs, and that AM with its potent anti-oxidant action inhibits redox-sensitive JNK activation and gene expression induced by Ang II. These data suggest that AM plays a protective role as an endogenous anti-oxidant in Ang II-induced vascular injury.
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