Understanding the role of NOS-3 in ventilator-induced lung injury: don't take NO for an answer.
Understanding the role of NOS-3 in ventilator-induced lung injury: don't take NO for an answer.
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了解 NOS-3 在呼吸机引起的肺损伤中的作用：不要将 NO 视为答案。
DOI：
10.1152/ajplung.00179.2010
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发表时间：
2010
期刊：
影响因子：
--
通讯作者：
Summar,Marshall
中科院分区：
文献类型：
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作者：
Ware,LorraineB;Summar,Marshall
尽管一氧化氮合酶 (NOS) 于 1989 年首次被描述 (12)，但这些复杂的酶仍未完全被了解，并且它们在人类肺部疾病中的作用仍不清楚。人类中已描述了三种 NOS 亚型：神经元或 nNOS (NOS-1)、诱导型或 iNOS (NOS-2) 以及内皮或 eNOS (NOS-3)。 NOS 的所有亚型都是具有还原酶结构域和加氧酶结构域的模块化酶。当还原酶和加氧酶结构域之间的电子转移耦合时，通过L-精氨酸氧化与O 2 还原的耦合催化从底物L-精氨酸合成一氧化氮(NO)和L-瓜氨酸。 NOS 单体的二聚化是 NO 合成所必需的，并且在血红素蛋白存在的情况下发生。 NOS 产物 NO 是一种普遍存在的信号分子，可调节血管张力和血流、白细胞粘附、血小板聚集和线粒体耗氧量 (9)。在多种条件下，NOS 紧密相连的还原酶和加氧酶功能可能会脱开，从而抑制 NO 产生。在非偶联条件下，NOS优先催化分子氧还原形成超氧离子。导致 NOS 解偶联的一个众所周知的因素是底物缺乏 (5)。 L-精氨酸是 NOS 合成 NO 的唯一已知底物。虽然 L-精氨酸不是必需氨基酸，但在代谢应激（例如脓毒症）的情况下可能会成为有条件必需的氨基酸。 L-精氨酸可以在体内通过精氨基琥珀酸合酶和精氨基琥珀酸裂合酶从尿素循环中间产物L-瓜氨酸（也由NOS产生）合成。导致瓜氨酸/精氨酸可用性减少的因素包括缺血再灌注和生理应激 (3, 13, 18)。导致 NOS 解偶联的第二个因素是 NOS 辅因子四氢生物蝶呤 (BH 4) 不足，该因子通常与加氧酶结构域结合 (22)。可导致 BH 4 减少的因素包括氧化应激 (8) 和缺血再灌注 (22)。活性氧还可以与 NO 反应形成过氧亚硝酸盐。过氧亚硝酸盐本身可以导致 NOS 解偶联。另一个可能导致 NOS 解偶联的因素是不对称二甲基精氨酸 (ADMA) 的内源产生，ADMA 是一种 NOS 竞争性抑制剂，已被证明会导致 NOS-3 解偶联 (2, 17)。 NOS 的慢性解偶联与多种人类疾病有关，包括糖尿病 (9)、高血压 (9) 和舒张功能障碍 (16)。
although nitric oxide synthases (NOSs) were first described in 1989 (12), these complex enzymes are still not fully understood, and their role in human lung disease remains unclear. Three NOS isoforms have been described in humans: neuronal or nNOS (NOS-1), inducible or iNOS (NOS-2), and endothelial or eNOS (NOS-3). All isoforms of NOS are modular enzymes with a reductase domain and an oxygenase domain. When electron transfer between the reductase and oxygenase domains is coupled, synthesis of nitric oxide (NO) and l-citrulline from the substrate l-arginine is catalyzed via coupling of l-arginine oxidation with O 2 reduction. Dimerization of NOS monomers is required for this NO synthesis and occurs in the presence of heme protein. The NOS product NO is a ubiquitous signaling molecule that regulates vascular tone and blood flow, leukocyte adhesion, platelet aggregation, and mitochondrial oxygen consumption (9).There are several conditions under which the tightly linked reductase and oxygenase functions of NOS can become uncoupled, inhibiting NO production. Under uncoupled conditions, NOS preferentially catalyzes the reduction of molecular oxygen to form superoxide ion. One well-described factor leading to NOS uncoupling is substrate deficiency (5). l-Arginine is the only known substrate for NO synthesis by NOS. Although not an essential amino acid, l-arginine can become conditionally essential in situations of metabolic stress such as sepsis. l-Arginine can be synthesized in vivo from the urea cycle intermediate product l-citrulline (also generated by NOS), by argininosuccinate synthase, and argininosuccinate lyase. Factors that lead to reductions in citrulline/arginine availability include ischemia reperfusion and physiological stress (3, 13, 18). A second factor that can lead to uncoupling of NOS is insufficiency of the NOS cofactor tetrahydrobiopterin (BH 4), which is normally bound to the oxygenase domain (22). Factors that can lead to reductions in BH 4 include oxidative stress (8) and ischemia reperfusion (22). Reactive oxygen species can also react with NO to form peroxynitrite. Peroxynitrite can, in and of itself, lead to uncoupling of NOS. Another factor that can contribute to NOS uncoupling is endogenous production of asymmetric dimethyl arginine (ADMA), a competitive inhibitor of NOS that has been shown to cause uncoupling of NOS-3 (2, 17). Chronic uncoupling of NOS has been implicated in several human diseases including diabetes (9), hypertension (9), and diastolic dysfunction (16).