NADPH oxidase and enhanced superoxide generation in intrauterine undernourished rats: involvement of the renin-angiotensin system
NADPH oxidase and enhanced superoxide generation in intrauterine undernourished rats: involvement of the renin-angiotensin system
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DOI：
10.1016/s0008-6363(03)00461-9
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发表时间：
2003-09-01
影响因子：
10.8
通讯作者：
Nigro, D
中科院分区：
文献类型：
--
作者：
Franco, MDP;Akamine, EH;Nigro, D
目的：我们先前报道宫内营养不良通过降低超氧化物歧化酶活性而增加氧化应激。在目前的研究中，我们测试了NADPH氧化酶、黄嘌呤氧化酶、环氧合酶或一氧化氮合酶是否与子宫内营养不良大鼠观察到的O-2(-)生成增加有关。此外，我们还研究了血管紧张素II(Ang II)通过激活NADPH氧化酶对O-2(-)产生的影响。方法：雌性妊娠Wistar大鼠在整个妊娠期分别饲喂正常饲料或正常摄入量的50%。16周龄时取材于活体荧光显微镜、微血管反应性、局部Ang II浓度及AT(1)、p22(Phox)和gp91(Phox)基因表达的研究。在这项研究中，只使用了雄性后代。结果：黄嘌呤氧化酶抑制剂口恶嘌醇、一氧化氮合酶抑制剂L-NAME或环氧合酶抑制剂双氯芬酸对肠系膜小动脉的超氧化物歧化无明显影响。因此，这些血管来源的超氧化物不是导致超氧化物浓度增加的原因。相比之下，NADPH氧化酶抑制剂apocynin的治疗显著减少了超氧化物的产生，并改善了血管功能。另一方面，宫内营养不良并未改变p22(Phox)和gp91(Phox)的基因表达。用氯沙坦阻断AT受体后，局部Ang II浓度升高，氧化应激减轻，提示Ang II可诱导宫内营养不良大鼠产生O-2。结论：抑制NADPH氧化酶可减少宫内营养不良大鼠超氧阴离子的产生，改善血管功能。虽然目前还不清楚是什么机制导致了NADPH氧化酶活性的增加，但已经提出了Ang II通过激活NADPH氧化酶而产生超氧化物歧化的作用。(C)2003年欧洲心脏病学会。爱思唯尔出版，版权所有。
Objective: We previously reported that intrauterine undernutrition increased the oxidative stress by decreasing superoxide dismutase activity. In the present study, we tested whether NADPH oxidase, xanthine oxidase, cyclooxygenase or nitric oxide synthase are responsible for the increased O-2(-) generation observed in rats submitted to intrauterine undernutrition. In addition, we investigated the 2 effect of angiotensin II (ANG II on O-2(-) production via activation of NADPH oxidase. Methods: Female pregnant Wistar rats were fed either normal or 50% of the normal intake diets, during the whole gestational period. At 16 weeks of age, the rats were used for the study of intravital fluorescence microscopy; microvascular reactivity, local ANG II concentration and AT(1), p22(phox) and gp91(phox) gene expression. In this study only the male offspring was used. Results: Treatment of mesenteric arterioles with the xanthine oxidase inhibitor oxypurinol, the nitric oxide synthase inhibitor L-NAME or the cyclooxygenase, inhibitor diclofenac did not significantly change superoxide production. Thus, these vascular sources of superoxide were not responsible for the increased superoxide concentration. In contrast, treatment with the NADPH oxidase inhibitor apocynin significantly decreased superoxide generation and improved vascular function. On the other hand, intrauterine undernutrition did not alter the gene expression for p22(phox) and gp91(phox). The fact that the local ANG II concentration was increased and the attenuation of oxidative stress by blocking AT, receptor with losartan, led us to suggest that ANG II induces O-2 generation in intrauterine undernourished rats. Conclusion: Our study shows that NADPH oxidase inhibition attenuated superoxide anion generation and ameliorated vascular function in rats submitted to intrauterine undernutrition. Although it is not clear which mechanisms are responsible for the increase in NADPH oxidase activity, a role for ANG II-mediated superoxide production via activation of NADPH oxidase is suggested. (C) 2003 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.