Kadoguchi Tomoyasu, Shimada Kazunori, Koide Hiroshi, Miyazaki Tetsuro, Shiozawa Tomoyuki, Takahashi Shuhei, Aikawa Tatsuro, Ouchi Shohei, Kitamura Kenichi, Sugita Yurina, Hamad Al Shahi, Kunimoto Mitsuhiro, Sato-Okabayashi Yayoi, Akita Koji, Isoda Kikuo, Daida Hiroyuki
Department of Cardiovascular Medicine, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
Sportology Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
Front Physiol. 2018 Apr 5;9:340. doi: 10.3389/fphys.2018.00340. eCollection 2018.
Muscle wasting is a debilitating phenotype associated with chronic heart failure (CHF). We have previously demonstrated that angiotensin II (AII) directly induces muscle wasting in mice through the activation of NADPH oxidase (Nox). In this study, we tested the hypothesis that deficiency of NADPH oxidase 4 (Nox4), a major source of oxidative stress, ameliorates AII-induced muscle wasting through the regulation of redox balance. Nox4 knockout (KO) and wild-type (WT) mice were used. At baseline, there were no differences in physical characteristics between the WT and KO mice. Saline (vehicle, V) or AII was infused via osmotic minipumps for 4 weeks, after which, the WT + AII mice showed significant increases in Nox activity and NOX4 protein compared with the WT + V mice, as well as decreases in body weight, gastrocnemius muscle weight, and myocyte cross-sectional area. These changes were significantly attenuated in the KO + AII mice (27 ± 1 vs. 31 ± 1 g, 385 ± 3 vs. 438 ± 13 mg, and 1,330 ± 30 vs. 2281 ± 150 μm, respectively, all < 0.05). The expression levels of phospho-Akt decreased, whereas those of muscle RING Finger-1 (MuRF-1) and MAFbx/atrogin-1 significantly increased in the WT + AII mice compared with the WT + V mice. Furthermore, nuclear factor erythroid-derived 2-like 2 (Nrf2) and the expression levels of Nrf2-regulated genes significantly decreased in the WT + AII mice compared with the WT + V mice. These changes were significantly attenuated in the KO + AII mice ( < 0.05). Nox4 deficiency attenuated AII-induced muscle wasting, partially through the regulation of Nrf2. The Nox4-Nrf2 axis may play an important role in the development of AII-induced muscle wasting.
肌肉萎缩是一种与慢性心力衰竭（CHF）相关的使人衰弱的表型。我们之前已经证明，血管紧张素II（AII）通过激活NADPH氧化酶（Nox）直接诱导小鼠肌肉萎缩。在本研究中，我们检验了以下假设：作为氧化应激的主要来源，NADPH氧化酶4（Nox4）的缺乏通过调节氧化还原平衡改善AII诱导的肌肉萎缩。使用了Nox4基因敲除（KO）小鼠和野生型（WT）小鼠。在基线时，WT和KO小鼠的身体特征没有差异。通过渗透微型泵输注生理盐水（载体，V）或AII，持续4周，之后，与WT + V小鼠相比，WT + AII小鼠的Nox活性和NOX4蛋白显著增加，同时体重、腓肠肌重量和肌细胞横截面积减少。这些变化在KO + AII小鼠中显著减轻（分别为27±1 vs. 31±1 g、385±3 vs. 438±13 mg和1330±30 vs. 2281±150μm，均P<0.05）。与WT + V小鼠相比，WT + AII小鼠中磷酸化Akt的表达水平降低，而肌肉环指蛋白1（MuRF-1）和MAFbx/萎缩基因1的表达水平显著增加。此外，与WT + V小鼠相比，WT + AII小鼠中核因子红细胞衍生2样2（Nrf2）及其调控基因的表达水平显著降低。这些变化在KO + AII小鼠中显著减轻（P<0.05）。Nox4缺乏减轻了AII诱导的肌肉萎缩，部分是通过调节Nrf2实现的。Nox4-Nrf2轴可能在AII诱导的肌肉萎缩发展中起重要作用。
