Early determinants of H2O2-induced endothelial dysfunction
Early determinants of H2O2-induced endothelial dysfunction
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DOI：
10.1016/j.freeradbiomed.2006.05.030
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发表时间：
2006-09-01
影响因子：
7.4
通讯作者：
Dudley, Samuel C., Jr.
中科院分区：
文献类型：
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作者：
Boulden, Beth M.;Widder, Julian D.;Dudley, Samuel C., Jr.
活性氧种(ROS)通过瞬时激活内皮型一氧化氮合酶(ENOS)，刺激内皮细胞产生一氧化氮(NO中心点)。然而，在连续或重复曝光的情况下，没有中心点的产生减少。我们研究了无中心网点产生减少的早期决定因素。在最初的过氧化氢暴露后，内皮细胞的反应是增加了电化学测量的NO中心点的产生。NO中心点浓度在10min时达到峰值，30min后缓慢下降。30min时NO中心点的减少与O-2(中心点-)产量增加2.7倍(P<；0.05)和eNOS辅因子四氢生物蝶呤(BH4，P<；0.05)减少14倍有关。作为内皮功能障碍的探针，重复过氧化氢暴露30min后，整合的NO中心点的产生减少了2.1倍(P=0.03)。补充BH4辅因子，清除O-2(中心点-)或过氧亚硝酸盐(ONOO-)，或抑制NADPH氧化酶，可以预防内皮功能障碍。羟基自由基((OH)-O-中心点)清除作用不明显。综上所述，早期过氧化氢诱导的内皮功能障碍与BH4水平降低和O-2(中心点-)产生增加有关。功能障碍需要O-2(中心点-)、ONOO-或功能性NADPH氧化酶。ROS反复激活NADPH氧化酶可能是促进内皮功能障碍的前馈系统。(C)2006 Elsevier Inc.保留所有权利。
Reactive oxygen species (ROS) can stimulate nitric oxide (NO center dot) production from the endothelium by transient activation of endothelial nitric oxide synthase (eNOS). With continued or repeated exposure, NO center dot production is reduced, however. We investigated the early determinants of this decrease in NO center dot production. Following an initial H2O2 exposure, endothelial cells responded by increasing NO center dot production measured electrochemically. NO center dot concentrations peaked by 10 min with a slow reduction over 30 min. The decrease in NO center dot at 30 min was associated with a 2.7-fold increase in O-2(center dot-) production (p < 0.05) and a 14-fold reduction of the eNOS cofactor, tetrahydrobiopterin (BH4, P < 0.05). Used as a probe for endothelial dysfunction, the integrated NO center dot production over 30 min upon repeated H2O2 exposure was attenuated by 2.1-fold (P = 0.03). Endothelial dysfunction could be prevented by BH4 cofactor supplementation, by scavenging O-2(center dot-) or peroxynitrite (ONOO-), or by inhibiting the NADPH oxidase. Hydroxyl radical ((OH)-O-center dot) scavenging did not have an effect. In summary, early H2O2-induced endothelial dysfunction was associated with a decreased BH4 level and increased O-2(center dot-) production. Dysfunction required O-2(center dot-), ONOO-, or a functional NADPH oxidase. Repeated activation of the NADPH oxidase by ROS may act as a feed forward system to promote endothelial dysfunction. (c) 2006 Elsevier Inc. All rights reserved.