Tianjin Key Laboratory of Metabolic Diseases, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Center for Cardiovascular Diseases, Research Center of Basic Medical Sciences, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 300070, China.
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
Free Radic Biol Med. 2021 Sep;173:7-18. doi: 10.1016/j.freeradbiomed.2021.06.033. Epub 2021 Jul 9.
Myocardial ischemia/reperfusion injury (MIRI) is closely related to oxidative stress. However, the redox environment of the heart has not been evaluated thoroughly after MIRI, which limits precise redox intervention. In this study, we developed the redox environment metabolomic evaluation (REME) method to analyze the redox metabolites of the heart after MIRI. Based on the targeted metabolomics strategy, we established a detection panel for 22 redox-related molecules, including the major redox couples nicotinamide adenine dinucleotide (NADH/NAD+), nicotinamide adenine dinucleotide phosphate (NADPH/NADP+), and glutathione/glutathione disulfide (GSH/GSSG), reactive oxygen and nitrogen species-related molecules, and some lipid peroxidation products. The high sensitivity and specificity of the method make it suitable for evaluating the endogenous redox environment. The REME method showed that the heart tissue in a MIRI mouse model had a different redox profile from that in the control group. Different redox species changed in different ways. The ratios of GSSG/GSH and NADP+/NADPH increased, but the levels of both NAD+ and NADH decreased in the risk area of the infarcted heart after reperfusion. In addition, some reactive nitrogen species-related metabolites (tetrahydrobiopterin, arginine, and S-nitrosoglutathione) decreased and some lipid peroxides (4-hydroxy-2-nonenal, 4-hydroxy-2-hexenal, and benzaldehyde) increased. The redox metabolites GSH, GSSG, NADPH, NAD+, S-nitrosoglutathione, arginine, and tetrahydrobiopterin had a positive correlation with the ejection fraction and a negative correlation with the level of lactate dehydrogenase in plasma. In summary, we achieved a comprehensive, systemic understanding of the changes in the redox environment after MIRI. Our REME method could be used to evaluate the redox environment in other processes.
心肌缺血/再灌注损伤（MIRI）与氧化应激密切相关。然而，MIRI 后心脏的氧化还原环境尚未得到充分评估，这限制了精确的氧化还原干预。在这项研究中，我们开发了氧化还原环境代谢组学评估（REME）方法来分析 MIRI 后心脏的氧化还原代谢物。基于靶向代谢组学策略，我们建立了一个检测面板，用于检测 22 个氧化还原相关分子，包括主要的氧化还原对烟酰胺腺嘌呤二核苷酸（NADH/NAD+）、烟酰胺腺嘌呤二核苷酸磷酸（NADPH/NADP+）和谷胱甘肽/谷胱甘肽二硫化物（GSH/GSSG）、活性氧和氮物种相关分子以及一些脂质过氧化产物。该方法具有高灵敏度和特异性，适用于评估内源性氧化还原环境。REME 方法表明，MIRI 小鼠模型的心脏组织具有与对照组不同的氧化还原特征。不同的氧化还原物质以不同的方式变化。再灌注后梗死心脏风险区域的 GSSG/GSH 和 NADP+/NADPH 比值增加，但 NAD+和 NADH 的水平降低。此外，一些活性氮物种相关代谢物（四氢生物蝶呤、精氨酸和 S-亚硝基谷胱甘肽）减少，一些脂质过氧化物（4-羟基-2-壬烯醛、4-羟基-2-己烯醛和苯甲醛）增加。氧化还原代谢物 GSH、GSSG、NADPH、NAD+、S-亚硝基谷胱甘肽、精氨酸和四氢生物蝶呤与射血分数呈正相关，与血浆中乳酸脱氢酶水平呈负相关。总之，我们全面系统地了解了 MIRI 后氧化还原环境的变化。我们的 REME 方法可用于评估其他过程中的氧化还原环境。
