Apoptotic cascade initiated by angiotensin II in neonatal cardiomyocytes: role of DNA damage.
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.
Grishko
Valentina
V
Department of Pharmacology, University of South Alabama School of Medicine, Mobile, AL 36688, USA.
Pastukh
Viktor
V
Solodushko
Viktoriya
V
Gillespie
Mark
M
Azuma
Junichi
J
Schaffer
Stephen
S
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001483:Base Sequence; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D004249:DNA Damage / Q000502:physiology*; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000201:enzymology; D019255:NADPH Oxidases / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D011493:Protein Kinase C / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein
D004272:DNA, Mitochondrial; D005609:Free Radicals; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D014662:Vasoconstrictor Agents; D051028:bcl-2-Associated X Protein; D000804:Angiotensin II; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D019255:NADPH Oxidases; D011493:Protein Kinase C; C506435:Casp9 protein, rat; D053453:Caspase 9; D020169:Caspases