Gajos-Draus Anna, Duda Monika, Beręsewicz Andrzej
Department of Clinical Physiology, Postgraduate Medical School, Warsaw, Poland.
Department of Clinical Physiology, Postgraduate Medical School, Warsaw, Poland
Physiol Rep. 2017 Nov;5(20). doi: 10.14814/phy2.13474. Epub 2017 Oct 29.
The superoxide-forming NADPH oxidase homologues, Nox1, Nox2, and Nox5, seem to mediate the pro-atherosclerotic vascular phenotype. The hydrogen peroxide-forming Nox4 afforded vascular protection, likely via NF-E2-related factor-2 (Nrf2) activation and/or Nox2 downregulation in transgenic mice. We hypothesized that oxidative stress in the intact vasculature involves, aside from the upregulation of the superoxide-forming Noxs, the downregulation of the Nox4/Nrf2 pathway. Guinea-pigs and rats were studied either in winter or in summer, and the streptozotocin diabetic rats in winter. Plasma nitrite, and superoxide production by isolated hearts were measured, while frozen tissues served in biochemical analyses. Summer in both species and diabetes in rats downregulated myocardial Nox4 while reciprocally upregulating Nox2 and Nox5 in guinea-pigs, and Nox2 in rats. Simultaneously, myocardial Nrf2 activity and the expression of the Nrf2-directed heme oxygenase-1 and endothelial NO synthase were reduced while activity of the nuclear factor B (NF-B) and the expression of NF-B-directed inducible NO synthase and the vascular cell adhesion molecule-1 were increased. Cardiac superoxide production was increased while plasma nitrite was decreased reciprocally. Analogous disregulation of Noxs, Nrf2, and NF-B, occurred in diabetic rat kidneys. Given the diversity of the experimental settings and the uniform pattern of the responses, we speculate that: (1) chronic vascular oxidative stress is a nonspecific (model-, species-, organ-independent) response involving the induction of Nox2 (and Nox5 in guinea-pigs) and the NF-B pathway, and the repression of Nox4 and the Nrf2 pathway; and (2) the systems Nox2-NF-B and Nox4-Nrf2 regulate each other negatively.
生成超氧化物的烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶同系物Nox1、Nox2和Nox5似乎介导了动脉粥样硬化的血管表型。生成过氧化氢的Nox4能提供血管保护作用，这可能是通过在转基因小鼠中激活NF-E2相关因子2（Nrf2）和/或下调Nox2来实现的。我们推测，在完整的脉管系统中，氧化应激除了涉及生成超氧化物的Noxs上调外，还涉及Nox4/Nrf2途径的下调。我们在冬季或夏季对豚鼠和大鼠进行了研究，并在冬季对链脲佐菌素诱导的糖尿病大鼠进行了研究。测量了血浆亚硝酸盐以及离体心脏产生的超氧化物，同时将冷冻组织用于生化分析。在这两个物种中，夏季以及大鼠的糖尿病状态均下调了心肌Nox4，而在豚鼠中则上调了Nox2和Nox5，在大鼠中上调了Nox2。同时，心肌Nrf2活性以及Nrf2指导的血红素加氧酶-1和内皮型一氧化氮合酶的表达降低，而核因子κB（NF-κB）的活性以及NF-κB指导的诱导型一氧化氮合酶和血管细胞黏附分子-1的表达增加。心脏超氧化物的产生增加，而血浆亚硝酸盐则相应减少。在糖尿病大鼠肾脏中也出现了类似的Noxs、Nrf2和NF-κB失调情况。鉴于实验设置的多样性以及反应模式的一致性，我们推测：（1）慢性血管氧化应激是一种非特异性（与模型、物种、器官无关）反应，涉及Nox2（以及豚鼠中的Nox5）和NF-κB途径的诱导，以及Nox4和Nrf2途径的抑制；（2）Nox2-NF-κB和Nox4-Nrf2系统相互负调节。
