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1 Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa, United States
2 Integrated DNA Technologies, Coralville, Iowa, United States
3 Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa, United States; The Cardiovascular Center, University of Iowa, Iowa City, Iowa, United States
4 Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa, United States; The Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, Iowa City, Iowa, United States; The Cardiovascular Center, University of Iowa, Iowa City, Iowa, United States
* To whom correspondence should be addressed. E-mail: robin-davisson{at}uiowa.edu.
Angiotensin II (Ang II) has profound effects on the development and progression of pathological cardiac hypertrophy, however the intracellular signaling mechanisms are not fully understood. In this study, we used genetic tools to test the hypothesis that increased formation of superoxide (O2.-) radicals from a Rac1-regulated Nox2-containing NADPH oxidase is a key upstream mediator of Ang II-induced activation of serine-threonine kinase Akt, and that this signaling cascade plays a crucial role in Ang II-dependent cardiomyocyte hypertrophy. Ang II caused a significant time-dependent increase in Rac1 activation and O2.- production in primary neonatal rat cardiomyocytes, and these responses were abolished by adenoviral (Ad)-mediated expression of a dominant-negative Rac1 (AdN17Rac1) or cytoplasmic Cu/ZnSOD (AdCu/ZnSOD). Moreover, both AdN17Rac1 and AdCu/ZnSOD significantly attenuated Ang II-stimulated increases in cardiomyocyte size. Quantitative real-time PCR analysis demonstrated that Nox2 is the homologue expressed at highest levels in primary neonatal cardiomyocytes, and small interference RNA (siRNA) directed against it selectively decreased Nox2 expression by greater than 95% and abolished both Ang II-induced O2.- generation and cardiomyocyte hypertrophy. Finally, Ang II caused a time-dependent increase in Akt activity via activation of AT1 receptors, and this response was abolished by Ad-mediated expression cytosolic human O2.- dismutase (AdCu/ZnSOD). Furthermore, pretreatment of cardiomyocytes with dominant-negative Akt (AdDNAkt) abolished Ang II-induced cellular hypertrophy. These findings suggest that O2.- generated by a Nox2-containing NADPH oxidase is a central mediator of Ang II-induced Akt activation and cardiomyocyte hypertrophy, and that dysregulation of this signaling cascade may play an important role in cardiac hypertrophy.
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