Low levels of nitric oxide promotes heme maturation into several hemeproteins and is also therapeutic.
Low levels of nitric oxide promotes heme maturation into several hemeproteins and is also therapeutic.
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低水平的一氧化氮可促进血红素成熟成几种血蛋白，并且也具有治疗性。
DOI：
10.1016/j.redox.2022.102478
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发表时间：
2022-10
期刊：
影响因子：
11.4
通讯作者：
Stuehr, Dennis J.
中科院分区：
文献类型：
--
作者：
Ghosh, Arnab;Sumi, Mamta P.;Tupta, Blair;Okamoto, Toshihiro;Aulak, Kulwant;Tsutsui, Masato;Shimokawa, Hiroaki;Erzurum, Serpil C.;Stuehr, Dennis J.
一氧化氮 (NO) 是一种信号分子，在调节血管张力中发挥着关键作用，具有抗血小板和抗炎特性。虽然我们早期和当前的研究发现，低 NO 剂量会触发血红素快速插入未成熟的无血红素可溶性鸟苷酸环化酶 β 亚基 (apo-sGCβ)，从而形成成熟的 sGC-αβ 异二聚体，但最近的证据表明，低 NO 剂量也可以触发血红蛋白和肌红蛋白的血红素成熟。这种低NO现象不仅限于sGC和球蛋白，还发现所有三种一氧化氮合酶（iNOS、nNOS和eNOS）和髓过氧化物酶（MPO）中都存在这种现象。有趣的是，高剂量的 NO 会抑制这些血红素蛋白的血红素插入，这表明 NO 具有剂量依赖性双重作用，因为它可以通过两种方式诱导或抑制关键血红素蛋白的血红素成熟。虽然低 NO 刺激球蛋白的血红素插入需要 NO-sGC-cGMP 信号通路的存在，但 iNOS 血红素成熟也需要活性 sGC 的存在。在双重（n/eNOS−/−）和三重（n/i/eNOS−/−）NOS敲除小鼠的组织中，低NO的这些影响显着减弱，这些小鼠的肺sGC被发现不含血红素，并且发现来自心脏/肺的肌红蛋白或血红蛋白的血红素含量较低，这表明内源性NO的损失对整个动物产生全局性影响，并且低NO的这种影响对于血红素蛋白成熟既重要又具有生理相关性。研究还发现，在肺移植前，低 NO 水平对离体肺灌注 (EVLP) 系统具有预防缺血再灌注损伤的作用，这进一步表明低 NO 水平也具有治疗作用。低水平的 NO 能够通过需要 NO 触发血红素插入 sGCβ 的过程使球蛋白血红素成熟。 • 低NO 的这种效应也被发现发生在所有三种一氧化氮合酶(NOS) 和髓过氧化物酶(MPO) 中。 •来自n/eNOS−/− 和n/i/eNOS−/− 敲除小鼠的组织中球蛋白中的血红素水平较低，而sGC 基本上不含血红素。 • ppm 水平的低NO 也可作为EVLP 上肺部缺血再灌注损伤期间的治疗方法。
Nitric oxide (NO) is a signal molecule and plays a critical role in the regulation of vascular tone, displays anti-platelet and anti-inflammatory properties. While our earlier and current studies found that low NO doses trigger a rapid heme insertion into immature heme-free soluble guanylyl cyclase β subunit (apo-sGCβ), resulting in a mature sGC-αβ heterodimer, more recent evidence suggests that low NO doses can also trigger heme-maturation of hemoglobin and myoglobin. This low NO phenomena was not only limited to sGC and the globins, but was also found to occur in all three nitric oxide synthases (iNOS, nNOS and eNOS) and Myeloperoxidase (MPO). Interestingly high NO doses were inhibitory to heme-insertion for these hemeproteins, suggesting that NO has a dose-dependent dual effect as it can act both ways to induce or inhibit heme-maturation of key hemeproteins. While low NO stimulated heme-insertion of globins required the presence of the NO-sGC-cGMP signal pathway, iNOS heme-maturation also required the presence of an active sGC. These effects of low NO were significantly diminished in the tissues of double (n/eNOS−/−) and triple (n/i/eNOS−/−) NOS knock out mice where lung sGC was found be heme-free and the myoglobin or hemoglobin from the heart/lungs were found be low in heme, suggesting that loss of endogenous NO globally impacts the whole animal and that this impact of low NO is both essential and physiologically relevant for hemeprotein maturation. Effects of low NO were also found to be protective against ischemia reperfusion injury on an ex vivo lung perfusion (EVLP) system prior to lung transplant, which further suggests that low NO levels are also therapeutic. Low levels of NO enable heme-maturation of the globins by a process that required an NO triggered heme-insertion into sGCβ. •This effect of low NO was also found to occur for all three nitric oxide synthases (NOSs) and Myeloperoxidase (MPO). •Tissues from n/eNOS−/− and n/i/eNOS−/− knock out mice had low heme levels in the globins, while sGC was largely heme-free. •Low NO at ppm levels also manifests itself as a therapy during ischemic reperfusion injury of lungs on the EVLP.
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DOI：
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