Nox2-containing NADPH oxidase and Akt activation play a key role in angiotensin II-induced cardiomyocyte hypertrophy

Shawn D. Hingtgen, Xin Tian, Jusan Yang, Shannon M. Dunlay, Andrew S. Peek, Yihe Wu, Ram V. Sharma, John F. Engelhardt, Robin L. Davisson

Research output: Contribution to journalArticle

112 Scopus citations

Abstract

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 (O 2-.) 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 homolog expressed at highest levels in primary neonatal cardiomyocytes, and small interference RNA (siRNA) directed against it selectively decreased Nox2 expression by >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 of 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 O 2-. 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.

Original languageEnglish (US)
Pages (from-to)180-191
Number of pages12
JournalPhysiological Genomics
Volume26
Issue number3
DOIs
StatePublished - Aug 16 2006

Keywords

  • Dominant-negative Rac1
  • Oxidative stress
  • Renin-angiotensin system
  • Small interference RNA
  • Superoxide radicals

ASJC Scopus subject areas

  • Physiology
  • Genetics

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    Hingtgen, S. D., Tian, X., Yang, J., Dunlay, S. M., Peek, A. S., Wu, Y., Sharma, R. V., Engelhardt, J. F., & Davisson, R. L. (2006). Nox2-containing NADPH oxidase and Akt activation play a key role in angiotensin II-induced cardiomyocyte hypertrophy. Physiological Genomics, 26(3), 180-191. https://doi.org/10.1152/physiolgenomics.00029.2005