Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Nat Chem Biol. 2012 Aug;8(8):714-24. doi: 10.1038/nchembio.1018. Epub 2012 Jul 1.
An emerging aspect of redox signaling is the pathway mediated by electrophilic byproducts, such as nitrated cyclic nucleotide (for example, 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP)) and nitro or keto derivatives of unsaturated fatty acids, generated via reactions of inflammation-related enzymes, reactive oxygen species, nitric oxide and secondary products. Here we report that enzymatically generated hydrogen sulfide anion (HS(-)) regulates the metabolism and signaling actions of various electrophiles. HS(-) reacts with electrophiles, best represented by 8-nitro-cGMP, via direct sulfhydration and modulates cellular redox signaling. The relevance of this reaction is reinforced by the significant 8-nitro-cGMP formation in mouse cardiac tissue after myocardial infarction that is modulated by alterations in HS(-) biosynthesis. Cardiac HS(-), in turn, suppresses electrophile-mediated H-Ras activation and cardiac cell senescence, contributing to the beneficial effects of HS(-) on myocardial infarction-associated heart failure. Thus, this study reveals HS(-)-induced electrophile sulfhydration as a unique mechanism for regulating electrophile-mediated redox signaling.
氧化还原信号传递的一个新方面是由亲电副产物介导的途径，例如通过炎症相关酶、活性氧、一氧化氮和次级产物反应生成的硝化环核苷酸（例如，8-硝鸟苷 3'，5'-环单磷酸（8-硝-cGMP））和不饱和脂肪酸的硝基或酮基衍生物。在这里，我们报告说，酶促产生的硫化氢阴离子（HS(-)）调节各种亲电试剂的代谢和信号转导作用。HS(-)通过直接巯基化与亲电试剂（以 8-硝-cGMP 为最佳代表）反应，并调节细胞氧化还原信号转导。这种反应的相关性通过心肌梗死后小鼠心脏组织中 8-硝-cGMP 的大量形成得到加强，该形成可通过 HS(-)生物合成的改变来调节。反过来，心脏 HS(-)抑制亲电试剂介导的 H-Ras 激活和心脏细胞衰老，为 HS(-)对心肌梗死相关心力衰竭的有益作用做出贡献。因此，本研究揭示了 HS(-)诱导的亲电试剂巯基化作为调节亲电试剂介导的氧化还原信号传递的独特机制。
