Department of Periodontology and Operative Dentistry, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany.
Center for Biochemistry, Faculty of Medicine, University of Cologne, 50931 Cologne, Germany.
Int J Mol Sci. 2023 Jan 4;24(2):901. doi: 10.3390/ijms24020901.
The binding of nitric oxide (NO) to heme in the β subunit of soluble guanylyl cyclase (sGC) activates both the heterodimeric αβ and αβ isoforms of the enzyme, leading to the increased production of cGMP from GTP. In cultured human mast cells, exogenous NO is able to inhibit mast cell degranulation via NO-cGMP signaling. However, under inflammatory oxidative or nitrosative stress, sGC becomes insensitive to NO. The occurrence of mast cells in healthy and inflamed human tissues and the in vivo expression of the α and β subunits of sGC in human mast cells during inflammation remain largely unresolved and were investigated here. Using peroxidase and double immunohistochemical incubations, no mast cells were found in healthy dental pulp, whereas the inflammation of dental pulp initiated the occurrence of several mast cells expressing the α and β subunits of sGC. Since inflammation-induced oxidative and nitrosative stress oxidizes Fe to Fe in the β subunit of sGC, leading to the desensitization of sGC to NO, we hypothesize that the NO- and heme-independent pharmacological activation of sGC in mast cells may be considered as a regulatory strategy for mast cell functions in inflamed human dental pulp.
一氧化氮（NO）与可溶性鸟苷酸环化酶（sGC）β亚基中的血红素结合，激活酶的异二聚体αβ和αβ同工型，导致 GTP 生成 cGMP 的增加。在培养的人肥大细胞中，外源性 NO 通过 NO-cGMP 信号抑制肥大细胞脱颗粒。然而，在炎症氧化或硝化应激下，sGC 对 NO 变得不敏感。健康和炎症人类组织中肥大细胞的存在以及炎症期间人肥大细胞中 sGC 的 α 和 β 亚基的体内表达在很大程度上仍未得到解决，本研究对此进行了调查。使用过氧化物酶和双重免疫组织化学孵育，在健康的牙髓中未发现肥大细胞，而牙髓的炎症引发了几个表达 sGC 的 α 和 β 亚基的肥大细胞的出现。由于炎症诱导的氧化和硝化应激将 sGCβ 亚基中的 Fe 氧化为 Fe，导致 sGC 对 NO 的脱敏，我们假设肥大细胞中 sGC 的 NO 和血红素非依赖性药理学激活可以被认为是调节炎症人牙髓中肥大细胞功能的一种策略。
