Low levels of nitric oxide promotes heme maturation into several hemeproteins and is also therapeutic

• Published in: Redox biology Vol. 56; p. 102478
• Main Authors: Ghosh, Arnab, Sumi, Mamta P., Tupta, Blair, Okamoto, Toshihiro, Aulak, Kulwant, Tsutsui, Masato, Shimokawa, Hiroaki, Erzurum, Serpil C., Stuehr, Dennis J.
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.10.2022; Elsevier
• Subjects: Cell Signaling; Classification; Globins: hemeproteins; Heme; Inflammation; Myoblasts; Nitric oxide; Reperfusion; Research Paper; Reperfusion; Nitric oxide; Globins: hemeproteins; Heme; Classification; Cell Signaling; Inflammation; Myoblasts
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2022.102478

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. [Display omitted] •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.