Oxidative and nitrosative stress in pediatric pulmonary hypertension: Roles of endothelin-1 and nitric oxide
Oxidative and nitrosative stress in pediatric pulmonary hypertension: Roles of endothelin-1 and nitric oxide
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DOI：
10.1016/j.vph.2006.08.005
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发表时间：
2006-11-01
影响因子：
4
通讯作者：
Fineman, Jeffrey R.
中科院分区：
文献类型：
--
作者：
Black, Stephen M.;Fineman, Jeffrey R.
越来越多的研究表明，氧化应激参与了内皮功能障碍的发展和心血管疾病的发病机制。此外，这种氧化应激已被证明与内皮素-1（ET-1）和一氧化氮（NO）信号传导途径的改变有关，使得生物可利用的NO减少，ET-1信号传导增强。然而，最近的数据，从我们的团队和其他人，已经表明，氧化应激，ET-1，和NO的共同调节在一个复杂的方式，似乎是依赖于每个物种的细胞水平。因此，当ROS水平瞬时升高时，NO信号通过转录、转录后和翻译后机制增强。然而，在小儿肺动脉高压疾病，当活性氧（ROS）的增加是由ET-1介导的激活平滑肌细胞ETA亚型受体，NOS基因表达和NO信号减少。此外，氧化应激的增加可以刺激ET-1基因的表达和ET-1肽的分泌。最后，外源性NO的添加以及越来越多地用于肺动脉高压的治疗也可以通过激活ROS生成酶和通过诱导线粒体功能障碍而导致ROS生成增加。因此，本文将审查现有的数据有关的相互作用的氧化和亚硝化应激，内皮功能障碍，其作用的小儿肺动脉高压的病理生理。此外，我们将建议基础和临床研究的途径，这将是重要的开发新的肺动脉高压的治疗和预防策略，并解决一些剩余的临床问题，关于使用NO增强。(c)2006年爱思唯尔公司All rights reserved.
An increasing number of studies implicate oxidative stress in the development of endothelial dysfunction and the pathogenesis of cardiovascular disease. Further, this oxidative stress has been shown to be associated with alterations in both the endothelin-1 (ET-1) and nitric oxide (NO) signaling pathways such that bioavailable NO is decreased and ET-1 signaling is potentiated. However, recent data, from our groups and others, have shown that oxidative stress, ET-1, and NO are co-regulated in a complex fashion that appears to be dependent on the cellular levels of each species. Thus, when ROS levels are transiently elevated, NO signaling is potentiated through transcriptional, post-transcriptional, and post-translational mechanisms. However, in pediatric pulmonary hypertensive disorders, when reactive oxygen species (ROS) increases are sustained by ET-1 mediated activation of smooth muscle cell ETA subtype receptors, NOS gene expression and NO signaling are reduced. Further, increases in oxidative stress can stimulate both the expression of the ET-1 gene and the secretion of the ET-1 peptide. Finally, the addition of exogenous NO, and increasingly utilized therapy for pulmonary hypertension, can also lead to increases ROS generation via the activation of ROS generating enzymes and through the induction of mitochondrial dysfunction. Thus, this manuscript will review the available data regarding the interaction of oxidative and nitrosative stress, endothelial dysfunction, and its role in the pathophysiology of pediatric pulmonary hypertension. In addition, we will suggest avenues of both basic and clinical research that will be important to develop novel pulmonary hypertension treatment and prevention strategies, and resolve some of the remaining clinical issues regarding the use of NO augmentation. (c) 2006 Elsevier Inc. All rights reserved.