title: NADPH oxidase 4 induces cardiac fibrosis and hypertrophy through activating Akt/mTOR and NFκB signaling pathways.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: From the Department of Medicine, University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, TX. zhaoq3@uthscsa.edu.
authors.forename: Qingwei David
authors.initials: QD
authors.lastname: Zhao
authors.affiliation: From the Department of Medicine, University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, TX.
authors.forename: Suryavathi
authors.initials: S
authors.lastname: Viswanadhapalli
authors.affiliation: From the Department of Medicine, University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, TX.
authors.forename: Paul
authors.initials: P
authors.lastname: Williams
authors.affiliation: From the Department of Medicine, University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, TX.
authors.forename: Qian
authors.initials: Q
authors.lastname: Shi
authors.affiliation: From the Department of Medicine, University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, TX.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Tan
authors.affiliation: From the Department of Medicine, University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, TX.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Yi
authors.affiliation: From the Department of Medicine, University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, TX.
authors.forename: Basant
authors.initials: B
authors.lastname: Bhandari
authors.affiliation: From the Department of Medicine, University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, TX.
authors.forename: Hanna E
authors.initials: HE
authors.lastname: Abboud
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000096:biosynthesis*; D016328:NF-kappa B / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: NADPH oxidase; NFκB; fibrosis; hypertrophy; mTORC1; reactive oxygen species