Department of Biotechnology, Institute of Biology and Biotechnology, University of Rzeszow, Rzeszow, Poland.
Anesthesiology and Intensive Care Department with the Center for Acute Poisoning, St. Jadwiga Provincial Clinical Hospital, Rzeszow, Poland.
Aging (Albany NY). 2020 Jun 25;12(14):13924-13938. doi: 10.18632/aging.103604.
Remifentanil and other opioids are suggested to be protective against ischemia-reperfusion injury in animal models and coronary artery bypass surgery patients, however the molecular basis of such protection is far from being understood. In the present study, we have used a model of human cardiomyocytes treated with the hypoxia-mimetic agent cobalt chloride to investigate remifentanil preconditioning-based adaptive responses and underlying mechanisms. Hypoxic conditions promoted oxidative and nitrosative stress, p21-mediated cellular senescence and the activation of necroptotic pathway that was accompanied by a 2.2-, 9.6- and 8.2-fold increase in phosphorylation status of mixed lineage kinase domain-like pseudokinase (MLKL) and release of pro-inflammatory cytokine IL-8 and cardiac troponin I, a marker of myocardial damage, respectively. Remifentanil preconditioning was able to lower hypoxia-mediated protein carbonylation and limit MLKL-based signaling and pro-inflammatory response to almost normoxic control levels, and decrease hypoxia-induced pro-senescent activity of about 21% compared to control hypoxic conditions. In summary, we have shown for the first time that remifentanil can protect human cardiomyocytes against hypoxia-induced cellular senescence and necroptosis that may have importance with respect to the use of remifentanil to diminish myocardial ischemia and reperfusion injury in patients undergoing cardiac surgery.
瑞芬太尼和其他阿片类药物被认为对动物模型和冠状动脉旁路手术患者的缺血再灌注损伤具有保护作用，但这种保护的分子基础还远未被理解。在本研究中，我们使用了一种用缺氧模拟剂氯化钴处理的人心肌细胞模型，来研究瑞芬太尼预处理的适应性反应及其潜在机制。缺氧条件促进氧化和硝化应激、p21 介导的细胞衰老和坏死性途径的激活，这伴随着混合谱系激酶结构域样伪激酶 (MLKL) 的磷酸化状态分别增加 2.2、9.6 和 8.2 倍，以及促炎细胞因子白细胞介素 8 和心肌肌钙蛋白 I（心肌损伤的标志物）的释放分别增加 2.2、9.6 和 8.2 倍。瑞芬太尼预处理能够降低缺氧介导的蛋白羰基化，并限制 MLKL 信号通路和促炎反应，使其接近正常氧对照水平，与对照缺氧条件相比，降低缺氧诱导的约 21%的促衰老活性。总之，我们首次表明，瑞芬太尼可以保护人心肌细胞免受缺氧诱导的细胞衰老和坏死性凋亡，这对于使用瑞芬太尼减轻心脏手术患者的心肌缺血再灌注损伤可能具有重要意义。
