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Angiotensin II-dependent activation of NADPH oxidase 4 contributes to muscle wasting in mice via downregulation of NF-E2-related factor 2

Session Heart Failure: new targets for treatment

Speaker Tomoyasu Kadoguchi

Event : ESC Congress 2018

  • Topic : basic science
  • Sub-topic : Cardiac Biology and Physiology, Other
  • Session type : Abstract Session

Authors : T Kadoguchi (Tokyo,JP), K Shimada (Tokyo,JP), T Miyazaki (Tokyo,JP), T Aikawa (Tokyo,JP), S Ouchi (Tokyo,JP), K Kitamura (Tokyo,JP), M Kunimoto (Tokyo,JP), Y Sugita (Tokyo,JP), T Shiozawa (Tokyo,JP), K Isoda (Tokyo,JP), H Daida (Tokyo,JP)

Authors:
T. Kadoguchi1 , K. Shimada1 , T. Miyazaki1 , T. Aikawa1 , S. Ouchi1 , K. Kitamura1 , M. Kunimoto1 , Y. Sugita1 , T. Shiozawa1 , K. Isoda1 , H. Daida1 , 1Juntendo University, Department of Cardiovascular Medicine - Tokyo - Japan ,

Citation:
European Heart Journal ( 2018 ) 39 ( Supplement ), 643

Background: Muscle wasting is promoted by cardiovascular diseases such as chronic heart failure (CHF). Angiotensin II (Ang II), a key mediator of the renin–angiotensin system, plays an important role in the pathogenesis of CHF. We previously reported that Ang II-dependent NADPH oxidase activation is associated with muscle wasting in mice. In this study, we hypothesized that Ang II-dependent Nox4 isoform activation is associated with muscle wasting in mice via downregulation of nuclear factor erythroid 2-related factor 2 (Nrf2).

Methods: Twelve-week-old male Nox4 knockout (KO) mice and age-matched male wild-type (WT) mice were used in this study. Either saline (vehicle) or Ang II (1000 ng/kg/min) was infused into WT and Nox4 KO mice via subcutaneously implanted osmotic minipumps for four weeks. Experiments were performed in the following four groups: WT + vehicle, Nox4 KO + vehicle, WT + Ang II, and Nox4 KO + Ang II. Gastrocnemius muscle was removed from the lower limbs and used to analyze the total Nox activity, quantitative real-time PCR and western blot. To identify the function of Nox4 in skeletal muscles, we used mouse skeletal muscle-derived myocytes (C2C12) transfected by electroporation with Nox4 small interfering RNA (siRNA) or scrambled control siRNA. Once confluent, the cells were treated with or without Ang II (106 M) and collected 24 h after treatment.

Results: Four weeks after Ang II infusion, the WT + Ang II mice showed increased total Nox activity, which was attenuated in the Nox4 KO + Ang II mice, in the skeletal muscles (p<0.05). Body mass, gastrocnemius muscle mass, and myocyte cross-sectional area were all significantly decreased in the WT + Ang II mice compared with the WT + vehicle mice (all, p<0.05). These changes were significantly attenuated in the Nox4 KO + Ang II mice (all, p<0.05). The levels of phosphorylated protein kinase B (Akt), a key molecule involved in protein synthesis, decreased in the WT + Ang II mice, whereas the protein expression levels of muscle RING finger-1 (MuRF-1) and muscle atrophy F-box (MAFbx)/Atrogin-1, key molecules in protein degradation, significantly increased in the WT + Ang II mice compared with the WT + vehicle mice. Moreover, Nrf2 mRNA and protein expression levels in the nuclear fraction significantly decreased in the WT + Ang II mice compared with the WT + vehicle mice. These effects were all significantly ameliorated in the Nox4 KO + Ang II mice (all, p<0.05). Nox4 knockdown by siRNA treatment in C2C12 cells significantly attenuated Ang II-induced downregulation of phosphorylated Akt and upregulation of MuRF-1 and MAFbx/Atrogin-1 (p<0.05).

Conclusion: Ang II-dependent Nox4 activation is associated with muscle wasting via downregulation of Nrf2 signaling, suggesting that the Nox4–Nrf2 axis plays an important role in the development of muscle wasting.

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