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Am J Physiol Heart Circ Physiol 285: H2364-H2372, 2003. First published August 14, 2003; doi:10.1152/ajpheart.00408.2003
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Apoptotic cascade initiated by angiotensin II in neonatal cardiomyocytes: role of DNA damage

Valentina Grishko,1 Viktor Pastukh,1 Viktoriya Solodushko,1 Mark Gillespie,1 Junichi Azuma,2 and Stephen Schaffer1

1Department of Pharmacology, University of South Alabama College of Medicine, Mobile, Alabama 36688; and 2Department of Clinical Evaluation of Medicine and Therapeutics, Osaka University, Osaka 565-0871, Japan

Submitted 15 May 2003 ; accepted in final form 17 July 2003

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 inducible nitric oxide inhibitor aminoguanidine prevents angiotensin II-induced DNA damage and apoptosis. Second, based on ligation-mediated PCR, the pattern of angiotensin II-induced DNA damage resembles peroxynitritemediated damage rather than damage caused by either superoxide or nitric oxide. Third, angiotensin II activates p53 through the phosphorylation of Ser15 and Ser20, 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.

NADPH oxidase; peroxynitrite; p53; Bax; Bcl-2; mitochondrial DNA; inducible nitric oxide synthase


Address for reprint requests and other correspondence: S. Schaffer, Univ. of South Alabama School of Medicine, Dept. of Pharmacology, Mobile, AL 36688 (E-mail: sschaffe{at}jaguar1.usouthal.edu).




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