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Nox2-containing NADPH oxidase and Akt activation play a key role in angiotensin II-induced cardiomyocyte hypertrophy.
Physiol Genomics. 2006 Aug 16; 26(3):180-91.PG

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 AT(1) 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.

Authors+Show Affiliations

Department of Anatomy and Cell Biology, The Free Radical and Radiation Biology Program, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16670255

Citation

Hingtgen, Shawn D., et al. "Nox2-containing NADPH Oxidase and Akt Activation Play a Key Role in Angiotensin II-induced Cardiomyocyte Hypertrophy." Physiological Genomics, vol. 26, no. 3, 2006, pp. 180-91.
Hingtgen SD, Tian X, Yang J, et al. Nox2-containing NADPH oxidase and Akt activation play a key role in angiotensin II-induced cardiomyocyte hypertrophy. Physiol Genomics. 2006;26(3):180-91.
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), 180-91.
Hingtgen SD, et al. Nox2-containing NADPH Oxidase and Akt Activation Play a Key Role in Angiotensin II-induced Cardiomyocyte Hypertrophy. Physiol Genomics. 2006 Aug 16;26(3):180-91. PubMed PMID: 16670255.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Nox2-containing NADPH oxidase and Akt activation play a key role in angiotensin II-induced cardiomyocyte hypertrophy. AU - Hingtgen,Shawn D, AU - Tian,Xin, AU - Yang,Jusan, AU - Dunlay,Shannon M, AU - Peek,Andrew S, AU - Wu,Yihe, AU - Sharma,Ram V, AU - Engelhardt,John F, AU - Davisson,Robin L, Y1 - 2006/05/02/ PY - 2006/5/4/pubmed PY - 2006/10/13/medline PY - 2006/5/4/entrez SP - 180 EP - 91 JF - Physiological genomics JO - Physiol Genomics VL - 26 IS - 3 N2 - 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 AT(1) 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. SN - 1531-2267 UR - https://www.unboundmedicine.com/medline/citation/16670255/Nox2_containing_NADPH_oxidase_and_Akt_activation_play_a_key_role_in_angiotensin_II_induced_cardiomyocyte_hypertrophy_ L2 - https://journals.physiology.org/doi/10.1152/physiolgenomics.00029.2005?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -