Superoxide dismutase/catalase mimetic EUK-134 prevents diaphragm muscle weakness in monocrotalin-induced pulmonary hypertension.
Superoxide dismutase/catalase mimetic EUK-134 prevents diaphragm muscle weakness in monocrotalin-induced pulmonary hypertension.
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DOI：
10.1371/journal.pone.0169146
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Yamada T
中科院分区：
文献类型：
--
作者：
Himori K;Abe M;Tatebayashi D;Lee J;Westerblad H;Lanner JT;Yamada T
肺动脉高压（PH）患者存在吸气功能不全，这与膈肌内在收缩功能障碍有关。在这里，我们通过使用新型抗氧化剂EUK-134研究了氧化还原应激在ph诱导的膈肌无力中的作用。雄性Wistar大鼠随机分为对照组（CNT）、CNT + EUK-134组（CNT + EUK）、单草碱诱导PH组（PH）和PH + EUK组。单次腹腔注射苦杏仁碱（60 mg/kg体重）诱导PH。EUK-134 （3 mg/kg体重/天）是一种细胞渗透性超氧化物歧化酶（SOD）和过氧化氢酶的模拟物，在ph诱导后第一天开始每天腹腔注射。四周后，切除膈肌进行机械和生化分析。PH组膈肌束比强直力降低，NADPH氧化酶2/gp91phox、SOD2、过氧化氢酶蛋白表达增加；3-硝基酪氨酸含量与肌动蛋白聚集；谷胱甘肽氧化。用EUK-134处理可防止PH隔膜束的力降低和肌动蛋白修饰。这些数据表明，氧化还原应激在ph诱导的膈肌无力中起关键作用。因此，抗氧化治疗可能是PH患者吸气衰竭的一个有希望的策略。
Patients with pulmonary hypertension (PH) suffer from inspiratory insufficiency, which has been associated with intrinsic contractile dysfunction in diaphragm muscle. Here, we examined the role of redox stress in PH-induced diaphragm weakness by using the novel antioxidant, EUK-134. Male Wistar rats were randomly divided into control (CNT), CNT + EUK-134 (CNT + EUK), monocrotaline-induced PH (PH), and PH + EUK groups. PH was induced by a single intraperitoneal injection of monocrotaline (60 mg/kg body weight). EUK-134 (3 mg/kg body weight/day), a cell permeable mimetic of superoxide dismutase (SOD) and catalase, was daily intraperitoneally administered starting one day after induction of PH. After four weeks, diaphragm muscles were excised for mechanical and biochemical analyses. There was a decrease in specific tetanic force in diaphragm bundles from the PH group, which was accompanied by increases in: protein expression of NADPH oxidase 2/gp91phox, SOD2, and catalase; 3-nitrotyrosine content and aggregation of actin; glutathione oxidation. Treatment with EUK-134 prevented the force decrease and the actin modifications in PH diaphragm bundles. These data show that redox stress plays a pivotal role in PH-induced diaphragm weakness. Thus, antioxidant treatment can be a promising strategy for PH patients with inspiratory failure.