Inhibition of endogenous thioredoxin in the heart increases oxidative stress and cardiac hypertrophy.
Inhibition of endogenous thioredoxin in the heart increases oxidative stress and cardiac hypertrophy.
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DOI：
10.1172/jci17700
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发表时间：
2003-11
期刊：
影响因子：
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通讯作者：
Mitsutaka Yamamoto;Guiping Yang;C. Hong;Jing Liu;E. Holle;Xianzhong Yu;T. Wagner;S. Vatner;
中科院分区：
文献类型：
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作者：
Mitsutaka Yamamoto;Guiping Yang;C. Hong;Jing Liu;E. Holle;Xianzhong Yu;T. Wagner;S. Vatner;
硫氧还蛋白1（Trx 1）具有氧化还原敏感的半胱氨酸残基，在细胞中起抗氧化剂的作用。然而，在任何器官中，Trx 1对整体抗氧化机制的贡献程度都是未知的。我们产生了心脏特异性过表达Trx 1的显性阴性（DN）突变体（C32 S/C35 S）的转基因小鼠（Tg-DN-Trx 1小鼠），其中内源性Trx的活性降低。与非转基因（NTg）小鼠相比，Tg-DN-Trx 1小鼠心脏中的氧化应激标志物显着增加。Tg-DN-Trx 1小鼠表现出心脏肥大，基线时心脏功能维持不变。Tg-DN-Trx 1小鼠腹腔注射抗氧化剂N-2-巯基丙酰甘氨酸，使心肌肥大正常化。与NTg小鼠相比，Tg-DN-Trx 1小鼠胸主动脉结扎引起心肌氧化应激增加和心肌肥厚增强。相比之下，心脏特异性过表达野生型Trx 1的转基因小鼠在基线时未显示心脏肥大，但在压力超负荷时表现出肥大和氧化应激水平降低。这些结果表明，内源性Trx 1是细胞抗氧化机制的重要组成部分，并在体内调节心脏氧化应激中起着关键作用。此外，抑制心脏中的内源性Trx 1主要刺激肥大，无论是在基础条件下还是通过氧化还原敏感机制响应压力超负荷。
Thioredoxin 1 (Trx1) has redox-sensitive cysteine residues and acts as an antioxidant in cells. However, the extent of Trx1 contribution to overall antioxidant mechanisms is unknown in any organs. We generated transgenic mice with cardiac-specific overexpression of a dominant negative (DN) mutant (C32S/C35S) of Trx1 (Tg-DN-Trx1 mice), in which the activity of endogenous Trx was diminished. Markers of oxidative stress were significantly increased in hearts from Tg-DN-Trx1 mice compared with those from nontransgenic (NTg) mice. Tg-DN-Trx1 mice exhibited cardiac hypertrophy with maintained cardiac function at baseline. Intraperitoneal injection of N-2-mercaptopropionyl glycine, an antioxidant, normalized cardiac hypertrophy in Tg-DN-Trx1 mice. Thoracic aortic banding caused greater increases in myocardial oxidative stress and enhanced hypertrophy in Tg-DN-Trx1 compared with NTg mice. In contrast, transgenic mice with cardiac-specific overexpression of wild-type Trx1 did not show cardiac hypertrophy at baseline but exhibited reduced levels of hypertrophy and oxidative stress in response to pressure overload. These results demonstrate that endogenous Trx1 is an essential component of the cellular antioxidant mechanisms and plays a critical role in regulating oxidative stress in the heart in vivo. Furthermore, inhibition of endogenous Trx1 in the heart primarily stimulates hypertrophy, both under basal conditions and in response to pressure overload through redox-sensitive mechanisms.