Broad suppression of NADPH oxidase activity exacerbates ischemia/reperfusion injury through inadvertent downregulation of hypoxia-inducible factor-1α and upregulation of peroxisome proliferator-activated receptor-α.
Broad suppression of NADPH oxidase activity exacerbates ischemia/reperfusion injury through inadvertent downregulation of hypoxia-inducible factor-1α and upregulation of peroxisome proliferator-activated receptor-α.
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DOI：
10.1161/circresaha.111.300171
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发表时间：
2013-04-12
影响因子：
20.1
通讯作者：
Sadoshima J
中科院分区：
文献类型：
--
作者：
Matsushima S;Kuroda J;Ago T;Zhai P;Ikeda Y;Oka S;Fong GH;Tian R;Sadoshima J
Nox 2和Nox 4是NADPH氧化酶（Nox）家族的主要组成部分，在心脏中有目的地产生活性氧化物质（ROS），即O2−和H2 O2。Nox 2和Nox 4对缺血/再灌注（I/R）损伤的亚型特异性贡献知之甚少。我们使用功能丧失小鼠模型研究了Nox 2和Nox 4在介导I/R期间氧化应激和心肌损伤中的作用。对全身性（s）Nox 2 KO、sNox 4 KO和心脏特异性（c）Nox 4 KO小鼠进行I（30 min）/R（24 h）。与野生型（WT）小鼠相比，sNox 2 KO、sNox 4 KO和cNox 4 KO小鼠的心肌梗死面积/风险面积（MI/AAR）和O2−产生均较低。然而，出乎意料的是，在sNox 2 KO+ cNox 4 KO（DKO）小鼠和心脏特异性表达显性阴性Nox（Tg-DN-Nox）的转基因小鼠中，MI/AAR比WT或单一KO小鼠更大，尽管O2−产生较少。在Tg-DN-Nox小鼠中，缺氧诱导因子-1 α（HIF-1α）下调，而过氧化物酶体增殖物激活受体α（PPARα）上调。与缺乏脯氨酰羟化酶2（羟化HIF-1α）的小鼠杂交，挽救了Tg-DN-Nox小鼠的I/R损伤并阻止了PPARα的上调。与PPARα KO小鼠杂交也减轻了Tg-DN-Nox小鼠的损伤。Nox 2和Nox 4均参与了I/R引起的ROS增加和损伤。然而，由Nox 2或Nox 4产生的低水平ROS调节HIF-1α和PPARα，从而保护心脏免受I/R，这表明Nox也作为心肌适应的生理传感器。
Nox2 and Nox4 are major components of the NADPH oxidase (Nox) family, which purposefully produce reactive oxidative species (ROS), namely O2− and H2O2, in the heart. The isoform-specific contribution of Nox2 and Nox4 to ischemia/reperfusion (I/R) injury is poorly understood. We investigated the role of Nox2 and Nox4 in mediating oxidative stress and myocardial injury during I/R using loss of function mouse models. Systemic (s) Nox2 KO, sNox4 KO, and cardiac-specific (c) Nox4 KO mice were subjected to I (30 min)/R (24 h). Both myocardial infarct size/area at risk (MI/AAR) and O2− production were lower in sNox2 KO, sNox4 KO, and cNox4 KO than in wild-type (WT) mice. Unexpectedly, however, the MI/AAR was greater, despite less O2− production, in sNox2 KO+cNox4 KO (DKO) mice and transgenic mice with cardiac-specific expression of dominant-negative Nox (Tg-DN-Nox), which suppresses both Nox2 and Nox4, than in WT or single KO mice. Hypoxia-inducible factor-1α (HIF-1α) was downregulated while peroxisome proliferator-activated receptor-alpha (PPARα) was upregulated in Tg-DN-Nox mice. A cross with mice deficient in prolyl hydroxylase 2, which hydroxylates HIF-1α, rescued the I/R injury and prevented upregulation of PPARα in Tg-DN-Nox mice. A cross with PPARα KO mice also attenuated the injury in Tg-DN-Nox mice. nBoth Nox2 and Nox4 contribute to the increase in ROS and injury by I/R. However, low levels of ROS produced by either Nox2 or Nox4 regulate HIF-1α and PPARα, thereby protecting the heart against I/R, suggesting that Noxs also act as a physiological sensor for myocardial adaptation.