Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
Department of Physics, Wake Forest University, Winston-Salem, NC, USA.
Nat Chem Biol. 2023 Oct;19(10):1256-1266. doi: 10.1038/s41589-023-01413-3. Epub 2023 Sep 14.
Nitric oxide (NO) is an endogenously produced signaling molecule that regulates blood flow and platelet activation. However, intracellular and intravascular diffusion of NO are limited by scavenging reactions with several hemoproteins, raising questions as to how free NO can signal in hemoprotein-rich environments. We explore the hypothesis that NO can be stabilized as a labile ferrous heme-nitrosyl complex (Fe-NO, NO-ferroheme). We observe a reaction between NO, labile ferric heme (Fe) and reduced thiols to yield NO-ferroheme and a thiyl radical. This thiol-catalyzed reductive nitrosylation occurs when heme is solubilized in lipophilic environments such as red blood cell membranes or bound to serum albumin. The resulting NO-ferroheme resists oxidative inactivation, is soluble in cell membranes and is transported intravascularly by albumin to promote potent vasodilation. We therefore provide an alternative route for NO delivery from erythrocytes and blood via transfer of NO-ferroheme and activation of apo-soluble guanylyl cyclase.
一氧化氮（NO）是一种内源性信号分子，可调节血液流动和血小板激活。然而，NO 的细胞内和血管内扩散受到与几种血红素蛋白的清除反应的限制，这引发了关于在富含血红素蛋白的环境中自由 NO 如何发出信号的问题。我们探讨了这样一种假设，即 NO 可以作为不稳定的亚铁血红素-亚硝酰基配合物（Fe-NO，NO-亚铁血红素）而稳定下来。我们观察到 NO、不稳定的三价铁血红素（Fe）和还原型硫醇之间的反应，生成 NO-亚铁血红素和硫自由基。这种巯基催化的还原亚硝化作用发生在血红素溶解于亲脂性环境中（如红细胞膜）或与血清白蛋白结合时。生成的 NO-亚铁血红素能抵抗氧化失活，在细胞膜中溶解，并通过白蛋白在血管内运输，以促进强烈的血管扩张。因此，我们提供了一种替代途径，通过 NO-亚铁血红素的转移和脱辅基可溶性鸟苷酸环化酶的激活，从红细胞和血液中输送 NO。
