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NAD(P)H oxidase 4 plays a key role in Angiotensin II-induced protein degradation in skeletal muscle cells

Session Poster session 6

Speaker Tomoyasu Kadoguchi

Event : ESC Congress 2016

  • Topic : basic science
  • Sub-topic : Basic Science - Cardiac Biology and Physiology
  • Session type : Poster Session

Authors : T Kadoguchi (Tokyo,JP), KS Kazunori Shimada (Tokyo,JP), TS Tomoyuki Shiozawa (Tokyo,JP), ST Shuhei Takahashi (Tokyo,JP), AH Al Shahi Hamad (Tokyo,JP), TM Tetsuro Miyazaki (Tokyo,JP), KA Koji Akita (Tokyo,JP), KI Kikuo Isoda (Tokyo,JP), HD Hiroyuki Daida (Tokyo,JP)

T. Kadoguchi1 , K. Shimada1 , T. Shiozawa1 , S. Takahashi1 , H. Al Shahi1 , T. Miyazaki1 , K. Akita1 , K. Isoda1 , H. Daida1 , 1Juntendo University, Department of Cardiovascular Medicine - Tokyo - Japan ,

European Heart Journal ( 2016 ) 37 ( Abstract Supplement ), 1104

Background: Skeletal muscle atrophy is observed in aging and a variety of diseases, including chronic kidney disease and heart failure. We have previously reported that angiotensin II (Ang II), a key mediator of the renin–angiotensin system, directly induced skeletal muscle atrophy in mice. Here we hypothesized that the activation of NAD(P)H oxidase 4 by Ang II induces protein degradation via the ubiquitin–proteasome pathway in skeletal muscle cells.

Methods: Mouse skeletal muscle cells (C2C12) were cultured in Dulbecco's modified Eagle's medium. They were transfected by electroporation with Nox4 small interference RNA (siRNA) or scrambled control siRNA. Once confluent, the cells were treated with or without Ang II (10–8–10–6 M) and collected 24 h after treatment. NAD(P)H oxidase activity was measured by a lucigenin assay after the addition of NAD(P)H.

Results: Ang II treatment induced a dose-dependent increase of NAD(P)H oxidase activity with the lucigenin assay in C2C12 myoblasts. It also induced an increase of Nox4 gene expression levels (266%, p<0.05). Gene expression levels of muscle RING finger-1 (MuRF-1) and atrogin-1/MAFbx (Atrogin-1), which are key molecules in protein degradation, were significantly increased (MuRF-1, 385%; Atrogin-1, 149%; p<0.05). However, protein expression levels of phosphorylated Akt (Ser473), a key molecule in protein synthesis, were significantly decreased in Ang II-treated cells compared with those in controls (−28.4, p<0.05). Nox4 knockdown by siRNA treatment significantly inhibited Ang II-induced upregulation of MuRF-1 and Atrogin-1 (MuRF-1, −56%; Atrogin-1, −60%; p<0.05).

Conclusion: The deletion of Nox4 improved protein degradation via the ubiquitin–proteasome pathway and decreased protein synthesis induced by Ang II. This suggests that Nox4 plays an important role in the development of skeletal muscle atrophy.

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