Journal article
NADPH oxidase 4 induces cardiac fibrosis and hypertrophy through activating Akt/mTOR and NFκB signaling pathways
Circulation (New York, N.Y.), Vol.131(7), pp.643-655
02/17/2015
DOI: 10.1161/CIRCULATIONAHA.114.011079
PMCID: PMC4568756
PMID: 25589557
Abstract
NADPH oxidase 4 (Nox4) has been implicated in cardiac remodeling, but its precise role in cardiac injury remains controversial. Furthermore, little is known about the downstream effector signaling pathways activated by Nox4-derived reactive oxygen species in the myocardium. We investigated the role of Nox4 and Nox4-associated signaling pathways in the development of cardiac remodeling.
Cardiac-specific human Nox4 transgenic mice (c-hNox4Tg) were generated. Four groups of mice were studied: (1) control mice, littermates that are negative for hNox4 transgene but Cre positive; (2) c-hNox4 Tg mice; (3) angiotensin II (AngII)-infused control mice; and (4) c-hNox4Tg mice infused with AngII. The c-hNox4Tg mice exhibited an ≈10-fold increase in Nox4 protein expression and an 8-fold increase in the production of reactive oxygen species, and manifested cardiac interstitial fibrosis. AngII infusion to control mice increased cardiac Nox4 expression and induced fibrosis and hypertrophy. The Tg mice receiving AngII exhibited more advanced cardiac remodeling and robust elevation in Nox4 expression, indicating that AngII worsens cardiac injury, at least in part by enhancing Nox4 expression. Moreover, hNox4 transgene and AngII infusion induced the expression of cardiac fetal genes and activated the Akt-mTOR and NFκB signaling pathways. Treatment of AngII-infused c-hNox4Tg mice with GKT137831, a Nox4/Nox1 inhibitor, abolished the increase in oxidative stress, suppressed the Akt-mTOR and NFκB signaling pathways, and attenuated cardiac remodeling.
Upregulation of Nox4 in the myocardium causes cardiac remodeling through activating Akt-mTOR and NFκB signaling pathways. Inhibition of Nox4 has therapeutic potential to treat cardiac remodeling.
Details
- Title: Subtitle
- NADPH oxidase 4 induces cardiac fibrosis and hypertrophy through activating Akt/mTOR and NFκB signaling pathways
- Creators
- Qingwei David Zhao - South Texas Veterans Health Care SystemSuryavathi Viswanadhapalli - South Texas Veterans Health Care SystemPaul Williams - South Texas Veterans Health Care SystemQian Shi - South Texas Veterans Health Care SystemChunyan Tan - South Texas Veterans Health Care SystemXiaolan Yi - South Texas Veterans Health Care SystemBasant Bhandari - South Texas Veterans Health Care SystemHanna E Abboud - South Texas Veterans Health Care System
- Resource Type
- Journal article
- Publication Details
- Circulation (New York, N.Y.), Vol.131(7), pp.643-655
- DOI
- 10.1161/CIRCULATIONAHA.114.011079
- PMID
- 25589557
- PMCID
- PMC4568756
- ISSN
- 0009-7322
- eISSN
- 1524-4539
- Grant note
- R01DK033665 / NIDDK NIH HHS R01 DK033665 / NIDDK NIH HHS
- Language
- English
- Date published
- 02/17/2015
- Academic Unit
- Neuroscience and Pharmacology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984363170802771
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