title: Upregulation of Nox4 promotes angiotensin II-induced epidermal growth factor receptor activation and subsequent cardiac hypertrophy by increasing ADAM17 expression.
abstract: BACKGROUND
  Activation of epidermal growth factor receptor (EGFR) plays an important role in angiotensin II (Ang II)-induced cardiac hypertrophy, but little is known about the underlying mechanism that results in EGFR activation. In this study, we aimed to confirm the important role of nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) in Ang II-induced EGFR activation and subsequent cardiac hypertrophy by upregulating expression of a disintegrin and metalloproteinase (MMP)-17 (ADAM17).
  
  
  METHODS
  Small interference RNA (siRNA) was adopted to knock down ADAM17 or Nox4 expression. Nox4 plasmid was used to construct cardiomyocytes with Nox4 overexpression.
  
  
  RESULTS
  Nox4 and ADAM17 increased in an abdominal artery coarctation-induced model of myocardial hypertrophy. In vitro studies showed that Nox4 was required in Ang II-induced EGFR activation and subsequent myocardial hypertrophy. Nox4 siRNA and Nox4 overexpression demonstrated that Nox4 controlled the transcription and translation of ADAM17. Furthermore, we observed that the ratio of phosphor-EGFR (p-EGFR) to EGFR was significantly reduced by ADAM17 siRNA in hypertrophic cardiomyocytes. Enzyme-linked immunosorbent assay studies revealed that Nox4 and ADAM17 mediated the release of mature heparin-binding EGF-like growth factor (HB-EGF), which played a critical role in the Ang II-induced EGFR activation. Moreover, the results of reactive oxygen species (ROS) scavenging by N-acetyl cysteine (NAC) indicated that ROS were required in the Nox4-mediated upregulation of ADAM17 expression.
  
  
  CONCLUSIONS
  In summary, Nox4 is required in Ang II-induced EGFR activation and subsequent cardiac hypertrophy; it increased the expression of ADAM17, which induced the release of mature HB-EGF. ROS were also required in the Nox4-mediated upregulation of ADAM17 expression.
authors.affiliation: Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, PR China.
authors.forename: Si-Yu
authors.initials: SY
authors.lastname: Zeng
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: Shao-Rui
authors.initials: SR
authors.lastname: Chen
authors.forename: Qin
authors.initials: Q
authors.lastname: Li
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Wang
authors.forename: Jian
authors.initials: J
authors.lastname: Zou
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Cao
authors.forename: Jia-Ni
authors.initials: JN
authors.lastname: Luo
authors.forename: Hui
authors.initials: H
authors.lastname: Gao
authors.forename: Pei-Qing
authors.initials: PQ
authors.lastname: Liu
mesh_terms: D051722:ADAM Proteins / Q000096:biosynthesis / Q000235:genetics*; D000072198:ADAM17 Protein; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D006332:Cardiomegaly / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000096:biosynthesis / Q000235:genetics*; D012313:RNA / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; D012313:RNA; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498911:Nox4 protein, rat; D066246:ErbB Receptors; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606464:Adam17 protein, rat