Contributions of Nitric Oxide Synthases, Dietary Nitrite/Nitrate, and Other Sources to the Formation of NO Signaling Products
Contributions of Nitric Oxide Synthases, Dietary Nitrite/Nitrate, and Other Sources to the Formation of NO Signaling Products
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DOI：
10.1089/ars.2011.4156
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发表时间：
2012-08-01
影响因子：
6.6
通讯作者：
Feelisch, Martin
中科院分区：
文献类型：
--
作者：
Milsom, Alexandra B.;Fernandez, Bernadette O.;Feelisch, Martin
缺乏所有三种一氧化氮合酶（NOS）基因的小鼠仍然可以存活，即使一氧化氮合酶的主要下游靶点——可溶性胍基环化酶的缺失与预期寿命的显著缩短有关。此外，eNOS敲除中相对正常的血流反应通常归因于补偿机制，包括剩余NOS亚型的上调，但膳食亚硝酸盐/硝酸盐（NOx）可能有助于基础水平的NO信号传导，这一可能性从未被研究过。目的：本研究旨在研究一氧化氮信号产物（亚硝化和亚硝基化蛋白质）和一氧化氮代谢产物（亚硝酸盐、硝酸盐）如何受到一氧化氮缺失的影响，以及饮食中一氧化氮是否在任何缺乏中起补偿作用。具体来说，我们试图确定这些产物的深刻改变是否发生在NOS异构体的基因缺失、所有NOS活性的抑制、NOx限制或上述所有情况下。结果：我们的研究结果表明，虽然确实发生了一些显著的变化，但它们出奇地温和，并被划分为特定的组织。出乎意料的是，在eNOS敲除小鼠中，即使在对所有nos进行药理学抑制并限制其饮食中NOx的摄入后，no相关产物的水平仍然显著升高。创新/结论：这些发现表明，与nos或膳食NOx无关的一种尚未确定的NO来源可能在组织中维持基础NO信号传导。鉴于一氧化氮在健康和疾病中的氧化还原调节的重要性，确定一氧化氮产品这一额外来源的性质似乎很重要，因为它可能为纠正一氧化氮缺乏提供新的治疗途径。Antioxid。氧化还原信号，17,422-432。
Mice lacking all three nitric oxide synthase (NOS) genes remain viable even though deletion of the major downstream target of NO, soluble guanylyl cyclase, is associated with a dramatically shortened life expectancy. Moreover, findings of relatively normal flow responses in eNOS knockouts are generally attributed to compensatory mechanisms including upregulation of remaining NOS isoforms, but the alternative possibility that dietary nitrite/nitrate (NOx) may contribute to basal levels of NO signaling has never been investigated. Aim: The aim of the present study was to examine how NO signaling products (nitrosated and nitrosylated proteins) and NO metabolites (nitrite, nitrate) are affected by single NOS deletions and whether dietary NOx plays a compensatory role in any deficiency. Specifically, we sought to ascertain whether profound alterations of these products arise upon genetic deletion of either NOS isoform, inhibition of all NOS activity, NOx restriction, or all of the above. Results: Our results indicate that while some significant changes do indeed occur, they are surprisingly moderate and compartmentalized to specific tissues. Unexpectedly, even after pharmacological inhibition of all NOSs and restriction of dietary NOx intake in eNOS knockout mice significant levels of NO-related products remain. Innovation/Conclusion: These findings suggest that a yet unidentified source of NO, unrelated to NOSs or dietary NOx, may be sustaining basal NO signaling in tissues. Given the significance of NO for redox regulation in health and disease, it would seem to be important to identify the nature of this additional source of NO products as it may offer new therapeutic avenues for correcting NO deficiencies. Antioxid. Redox Signal. 17, 422-432.