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1 Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA
* To whom correspondence should be addressed. E-mail: chaoj{at}musc.edu.
Adrenomedullin (AM) has been shown to protect against cardiac remodeling. In this study, we investigated the potential role of AM in myocardial ischemia/reperfusion (I/R) injury through adenovirus-mediated gene delivery. One week after AM gene delivery, rats were subjected to a 30-minute coronary occlusion followed by a 2-hour reperfusion. AM gene transfer significantly reduced the ratio of infarct size/ischemic area at risk and the occurrence of sustained ventricular fibrillation compared to control rats. AM gene delivery also attenuated apoptosis assessed by both TUNEL assay and DNA laddering. The effect of AM gene transfer on infarct size, arrhythmia and apoptosis were abolished by an AM antagonist, calcitonin gene-related peptide, CGRP(8-37). Expression of human AM significantly increased cardiac cGMP levels and reduced superoxide production, superoxide density and NAD(P)H oxidase activities, p38 MAPK activation and bax levels. Moreover, AM increased Akt and Bad phosphorylation, and Bcl-2 levels, but decreased caspase-3 activation. These results indicate that AM protects against myocardial infarction, arrhythmia and apoptosis in I/R injury via suppression of oxidative stress-induced Bax and p38 MAPK phosphorylation, and activation of Akt-Bad-Bcl-2 signaling pathway. Successful application of this technology may have a protective effect in coronary artery diseases.
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