Cortese-Krott Miriam M, Kuhnle Gunter G C, Dyson Alex, Fernandez Bernadette O, Grman Marian, DuMond Jenna F, Barrow Mark P, McLeod George, Nakagawa Hidehiko, Ondrias Karol, Nagy Péter, King S Bruce, Saavedra Joseph E, Keefer Larry K, Singer Mervyn, Kelm Malte, Butler Anthony R, Feelisch Martin
Cardiovascular Research Laboratory, Department of Cardiology, Pneumology and Angiology, Medical Faculty, Heinrich Heine University of Düsseldorf, 40225 Dusseldorf, Germany;
Department of Nutrition, University of Reading, Whiteknights, Reading RG6 6AP, United Kingdom;
Proc Natl Acad Sci U S A. 2015 Aug 25;112(34):E4651-60. doi: 10.1073/pnas.1509277112. Epub 2015 Jul 29.
Experimental evidence suggests that nitric oxide (NO) and hydrogen sulfide (H2S) signaling pathways are intimately intertwined, with mutual attenuation or potentiation of biological responses in the cardiovascular system and elsewhere. The chemical basis of this interaction is elusive. Moreover, polysulfides recently emerged as potential mediators of H2S/sulfide signaling, but their biosynthesis and relationship to NO remain enigmatic. We sought to characterize the nature, chemical biology, and bioactivity of key reaction products formed in the NO/sulfide system. At physiological pH, we find that NO and sulfide form a network of cascading chemical reactions that generate radical intermediates as well as anionic and uncharged solutes, with accumulation of three major products: nitrosopersulfide (SSNO(-)), polysulfides, and dinitrososulfite [N-nitrosohydroxylamine-N-sulfonate (SULFI/NO)], each with a distinct chemical biology and in vitro and in vivo bioactivity. SSNO(-) is resistant to thiols and cyanolysis, efficiently donates both sulfane sulfur and NO, and potently lowers blood pressure. Polysulfides are both intermediates and products of SSNO(-) synthesis/decomposition, and they also decrease blood pressure and enhance arterial compliance. SULFI/NO is a weak combined NO/nitroxyl donor that releases mainly N2O on decomposition; although it affects blood pressure only mildly, it markedly increases cardiac contractility, and formation of its precursor sulfite likely contributes to NO scavenging. Our results unveil an unexpectedly rich network of coupled chemical reactions between NO and H2S/sulfide, suggesting that the bioactivity of either transmitter is governed by concomitant formation of polysulfides and anionic S/N-hybrid species. This conceptual framework would seem to offer ample opportunities for the modulation of fundamental biological processes governed by redox switching and sulfur trafficking.
实验证据表明，一氧化氮（NO）和硫化氢（H₂S）信号通路紧密相连，在心血管系统及其他部位，二者对生物反应存在相互抑制或增强作用。这种相互作用的化学基础尚不清楚。此外，多硫化物最近成为H₂S/硫化物信号传导的潜在介质，但其生物合成以及与NO的关系仍不明确。我们试图表征NO/硫化物系统中形成的关键反应产物的性质、化学生物学及生物活性。在生理pH值条件下，我们发现NO和硫化物形成了一个级联化学反应网络，该网络会生成自由基中间体以及阴离子和不带电的溶质，同时积累三种主要产物：亚硝基过硫化物（SSNO⁻）、多硫化物和二亚硝基亚硫酸盐[N-亚硝基羟胺-N-磺酸盐（SULFI/NO）]，每种产物都具有独特的化学生物学特性以及体外和体内生物活性。SSNO⁻对硫醇和氰解具有抗性，能有效提供硫烷硫和NO，并能显著降低血压。多硫化物既是SSNO⁻合成/分解的中间体也是产物，它们也能降低血压并增强动脉顺应性。SULFI/NO是一种较弱的NO/硝酰基组合供体，分解时主要释放N₂O；尽管它对血压的影响较小，但能显著增加心脏收缩力，其前体亚硫酸盐的形成可能有助于清除NO。我们的研究结果揭示了NO与H₂S/硫化物之间出人意料的丰富耦合化学反应网络，这表明任何一种递质的生物活性都受多硫化物和阴离子S/N杂化物种的伴随形成所支配。这一概念框架似乎为调控由氧化还原转换和硫转运所支配的基本生物过程提供了充足的机会。
