Journal article
Nox2-containing NADPH oxidase and Akt activation play a key role in angiotensin II-induced cardiomyocyte hypertrophy
Physiological genomics, Vol.26(3), pp.180-191
08/2006
DOI: 10.1152/physiolgenomics.00029.2005
PMID: 16670255
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 (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 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 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.
Details
- Title: Subtitle
- Nox2-containing NADPH oxidase and Akt activation play a key role in angiotensin II-induced cardiomyocyte hypertrophy
- Creators
- Shawn D Hingtgen - Department of Anatomy and Cell Biology, The Free Radical and Radiation Biology ProgramXin Tian - Department of Anatomy and Cell Biology, The Free Radical and Radiation Biology ProgramJusan Yang - Department of Anatomy and Cell Biology, The Free Radical and Radiation Biology ProgramShannon M Dunlay - Department of Anatomy and Cell Biology, The Free Radical and Radiation Biology ProgramAndrew S Peek - Integrated DNA Technologies, Coralville, IowaYihe Wu - Integrated DNA Technologies, Coralville, IowaRam V Sharma - Department of Anatomy and Cell Biology, The Free Radical and Radiation Biology Program, The Cardiovascular CenterJohn F Engelhardt - Department of Anatomy and Cell Biology, The Free Radical and Radiation Biology Program, Department of Radiation Oncology, The Cardiovascular Center, The Center for Gene Therapy of Cystic Fibrosis and Other Genetic Diseases, Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa CityRobin L Davisson - Department of Anatomy and Cell Biology, The Free Radical and Radiation Biology Program, Department of Radiation Oncology, The Cardiovascular Center, The Center for Gene Therapy of Cystic Fibrosis and Other Genetic Diseases
- Resource Type
- Journal article
- Publication Details
- Physiological genomics, Vol.26(3), pp.180-191
- DOI
- 10.1152/physiolgenomics.00029.2005
- PMID
- 16670255
- ISSN
- 1094-8341
- eISSN
- 1531-2267
- Language
- English
- Date published
- 08/2006
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Anatomy and Cell Biology; Radiation Oncology; Internal Medicine
- Record Identifier
- 9984025410202771
Metrics
20 Record Views