Institute of Physiology, The Czech Academy of Sciences, Prague, Czech Republic; Department of Physiology, Faculty of Science, Charles University in Prague, Prague, Czech Republic.
Acta Physiol (Oxf). 2015 May;214(1):97-108. doi: 10.1111/apha.12489. Epub 2015 Mar 28.
It has been demonstrated that tumour necrosis factor-alpha (TNF-α) via its receptor 2 (TNFR2) plays a role in the cardioprotective effects of preconditioning. It is also well known that chronic hypoxia is associated with activation of inflammatory response. With this background, we hypothesized that TNF-α signalling may contribute to the improved ischaemic tolerance of chronically hypoxic hearts.
Adult male Wistar rats were kept either at room air (normoxic controls) or at continuous normobaric hypoxia (CNH; inspired O2 fraction 0.1) for 3 weeks; subgroups of animals were treated with infliximab (monoclonal antibody against TNF-α; 5 mg kg(-1), i.p., once a week). Myocardial levels of oxidative stress markers and the expression of selected signalling molecules were analysed. Infarct size (tetrazolium staining) was assessed in open-chest rats subjected to acute coronary artery occlusion/reperfusion.
CNH increased myocardial TNF-α level and expression of TNFR2; this response was abolished by infliximab treatment. CNH reduced myocardial infarct size from 50.8 ± 4.3% of the area at risk in normoxic animals to 35.5 ± 2.4%. Infliximab abolished the protective effect of CNH (44.9 ± 2.0%). CNH increased the levels of oxidative stress markers (3-nitrotyrosine and malondialdehyde), the expression of nuclear factor κB and manganese superoxide dismutase, while these effects were absent in infliximab-treated animals. CNH-elevated levels of inducible nitric oxide synthase and cyclooxygenase 2 were not affected by infliximab.
TNF-α plays a role in the induction of ischaemia-resistant cardiac phenotype of CNH rats, possibly via the activation of protective redox signalling.
已经证明肿瘤坏死因子-α（TNF-α）通过其受体 2（TNFR2）在预处理的心脏保护作用中发挥作用。众所周知，慢性缺氧与炎症反应的激活有关。基于此背景，我们假设 TNF-α信号可能有助于慢性缺氧心脏的缺血耐受改善。
成年雄性 Wistar 大鼠分别在常氧（正常对照组）或持续常压缺氧（CNH；吸入 O2 分数 0.1）下饲养 3 周；部分动物接受英夫利昔单抗（抗 TNF-α的单克隆抗体；5mg/kg，腹腔注射，每周一次）治疗。分析心肌氧化应激标志物水平和选定信号分子的表达。在开胸大鼠中评估急性冠状动脉闭塞/再灌注后的梗塞面积（四唑染色）。
CNH 增加了心肌 TNF-α水平和 TNFR2 的表达；英夫利昔单抗治疗可消除这种反应。CNH 将正常氧动物心肌梗塞面积从 50.8±4.3%的危险区域减少到 35.5±2.4%。英夫利昔单抗消除了 CNH 的保护作用（44.9±2.0%）。CNH 增加了氧化应激标志物（3-硝基酪氨酸和丙二醛）、核因子 κB 和锰超氧化物歧化酶的表达，而在英夫利昔单抗治疗的动物中则没有这些作用。CNH 升高的诱导型一氧化氮合酶和环氧化酶 2水平不受英夫利昔单抗的影响。
TNF-α在 CNH 大鼠缺血耐受心脏表型的诱导中发挥作用，可能通过激活保护性氧化还原信号。
