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NADPH oxidase 4 induces muscle wasting via regulation of NF-E2-related factor 2 in angiotensin ii-infusion mice

Session Poster session 5

Speaker Tomoyasu Kadoguchi

Event : ESC Congress 2017

  • Topic : basic science
  • Sub-topic : Basic Science
  • Session type : Poster Session

Authors : T Kadoguchi (Tokyo,JP), K Shimada (Tokyo,JP), T Shiozawa (Tokyo,JP), S Takahashi (Tokyo,JP), A Hamad (Tokyo,JP), T Aikawa (Tokyo,JP), S Ouchi (Tokyo,JP), K Kitamura (Tokyo,JP), Y Sugita (Tokyo,JP), T Miyazaki (Tokyo,JP), K Akita (Tokyo,JP), K Isoda (Tokyo,JP), H Daida (Tokyo,JP)

T. Kadoguchi1 , K. Shimada1 , T. Shiozawa1 , S. Takahashi1 , A. Hamad1 , T. Aikawa1 , S. Ouchi1 , K. Kitamura1 , Y. Sugita1 , T. Miyazaki1 , K. Akita1 , K. Isoda1 , H. Daida1 , 1Juntendo University, Department of Cardiovascular Medicine - Tokyo - Japan ,

European Heart Journal ( 2017 ) 38 ( Supplement ), 938

Background: Muscle wasting is involved in chronic heart failure. We have previously revealed that angiotensin II (Ang II), a key mediator of the renin–angiotensin system, directly induced muscle wasting in mice via the activation of NADPH oxidase (Nox), a major source of oxidative stress. In this study, we hypothesized that Nox4 is associated with muscle wasting via regulation of NF-E2-Related Factor 2 (Nrf2) in Ang II-infusion mice.

Methods: Twelve-week old male Nox4 knockout (KO) mice and age-matched male wild-type (WT) mice were used. Either saline (vehicle) or Ang II (1000 ng/kg/min) was infused into WT and Nox4 KO mice via subcutaneously implanted osmotic minipumps for 4 weeks. Experiments were performed in the following 4 groups; WT + vehicle (n=7), Nox4 KO + vehicle (n=8), WT + Ang II (n=7), and Nox4 KO + Ang II (n=8). Skeletal muscles were removed from the lower limbs and used for the analysis of Nox activity, quantitative real-time PCR and western blot.

Results: At baseline, there were no differences in physical characteristics between WT and Nox4 KO mice. However, 4 weeks after Ang II-infusion, WT + Ang II mice showed an increased activation of Nox in the skeletal muscles that was inhibited in Nox4 KO + Ang II mice (p<0.05). Body and lower limb skeletal muscle weight, and myocyte cross-sectional area significantly decreased in WT + Ang II mice compared to WT + vehicle mice (27±1 vs. 31±1 g, 385±3 vs. 438±13 mg, and 1330±30 vs. 2281±150 μm2, respectively; all p values <0.05). These changes were significantly attenuated in Nox4 KO + Ang II mice (30±1 g, 447±9 mg, 2323±22 μm2, respectively; all p values <0.05). Protein expression level of phospho-Akt, a key molecule involved in protein synthesis, decreased in WT + Ang II mice, and muscle RING finger-1 and MAFbx/Atrogin-1, key molecules of protein degradation, significantly increased in WT + Ang II mice compared to WT + vehicle mice. Moreover, gene expression levels of Nrf2 and its regulated genes, and protein expression level of Nrf2 in nuclear fraction significantly decreased in WT + Ang II mice compared to WT + vehicle mice. These parameters were significantly ameliorated in Nox4 KO + Ang II mice (all p values <0.05).

Conclusion: Nox4 induces muscle wasting by Ang II via regulation of Nrf2 pathway, suggesting that the Nox4–Nrf2 axis plays an essential role in the development of muscle wasting.

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