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1 Department of Pharmacology, University of South Alabama, Mobile, AL, USA
2 Department of Clinical Evaluation of Medicine and Therapeutics, Osaka University, Osaka, Japan
* To whom correspondence should be addressed. E-mail: sschaffe{at}jaguar1.usouthal.edu.
Angiotensin II contributes to ventricular remodeling by promoting both cardiac hypertrophy and apoptosis, however, the mechanism underlying the latter phenomenon is poorly understood. One possibility that has been advanced is that angiotensin II activates NADPH oxidase, generating free radicals that trigger apoptosis. In apparent support of this notion, it was found that angiotensin II-mediated apoptosis in the cardiomyocyte is blocked by the NADPH oxidase inhibitor, diphenylene iodonium. However, three lines of evidence suggest that peroxynitrite, rather than superoxide, is responsible for angiotensin II-mediated DNA damage and apoptosis. First, the iNOS inhibitor, aminoguanidine, prevents angiotensin II-induced DNA damage, and apoptosis. Second, based on LM-PCR, the pattern of angiotensin II-induced DNA damage resembles peroxynitrite-mediated damage rather than damage caused by either superoxide or nitric oxide. Third, angiotensin II activates p53 through the phosphorylation of serine 15 and serine 20, residues that are commonly phosphorylated in response to DNA damage. It is proposed that angiotensin II promotes the oxidation of DNA, which in turn activates p53 to mediate apoptosis.
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