Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia and CIBERFES-ISCIII, Fundación Investigación Hospital Clínico Universitario/INCLIVA, Valencia, Spain.
Department of Cardiology, Hospital Clínico Universitario, INCLIVA, Valencia, Spain.
Free Radic Res. 2020 Mar;54(2-3):173-184. doi: 10.1080/10715762.2020.1735632. Epub 2020 Mar 10.
Reductive stress is defined as a pathophysiological situation in which the cell becomes more reduced than in the normal, resting state. It represents a disturbance in the redox state that is harmful to biological systems. Our aim was to study the occurrence of reductive stress in the early phases of experimental myocardial infarction and to determine the mechanisms leading to such stress using a swine model. During the ischemic period, we found a decrease in the oxidized to reduced glutathione ratio (GSSG/GSH) (0.7-0.3), in the lactate to pyruvate ratio (42.7-132.4), in protein glutathionylation (111.8-96.1), and in p38 phosphorylation (0.9-0.4). This was accompanied by a significant increase in the expression of Thioredoxin (TXN) (0.6-1.9) and peroxiredoxin (PRDX6) (0.6-1.6) in different left ventricle areas. After reperfusion, there was a massive increase in oxidative damage markers including lipid peroxidation (0.2-0.4), protein carbonylation (144.9-462.8), and glutathionylation (111.8-176.8). Concomitantly, we found an activation of nuclear factor erythroid 2-related factor 2 (Nrf2) (1.2-6.1) and of a set of antioxidant enzymes including TXN, PRDX6, glutathione peroxidase (GPX1), glutathione reductase (GSR), and glucose 6 phosphate dehydrogenase (G6PD). We describe an early reductive, followed by a late onset oxidative stress (1 week and 1 month after reperfusion) in a swine myocardial infarction model. The occurrence of an early reductive phase may explain the lack of effectiveness of antioxidant therapies when administered in the early phases after reperfusion of ischemic hearts.
还原性应激被定义为细胞比正常静息状态更还原的病理生理情况。它代表了对生物系统有害的氧化还原状态的紊乱。我们的目的是研究实验性心肌梗死早期阶段还原性应激的发生，并使用猪模型确定导致这种应激的机制。在缺血期间，我们发现氧化型谷胱甘肽与还原型谷胱甘肽的比值（GSSG/GSH）（0.7-0.3）、乳酸与丙酮酸的比值（42.7-132.4）、蛋白谷胱甘肽化（111.8-96.1）和 p38 磷酸化（0.9-0.4）下降。这伴随着不同左心室区域中硫氧还蛋白（TXN）（0.6-1.9）和过氧化物酶 6（PRDX6）（0.6-1.6）的表达显著增加。再灌注后，氧化损伤标志物包括脂质过氧化（0.2-0.4）、蛋白羰基化（144.9-462.8）和谷胱甘肽化（111.8-176.8）大量增加。同时，我们发现核因子红细胞 2 相关因子 2（Nrf2）（1.2-6.1）和一组抗氧化酶包括 TXN、PRDX6、谷胱甘肽过氧化物酶 1（GPX1）、谷胱甘肽还原酶（GSR）和葡萄糖 6 磷酸脱氢酶（G6PD）的激活。我们在猪心肌梗死模型中描述了早期的还原性应激，随后是晚期的氧化性应激（再灌注后 1 周和 1 个月）。早期还原性阶段的发生可能解释了在缺血性心脏再灌注的早期阶段给予抗氧化治疗无效的原因。
