Gao Sumin, Zhan Leyun, Yang Zhengchao, Shi Ruili, Li Haobo, Xia Zhengyuan, Yuan Shiying, Wu Qing-Ping, Wang Tingting, Yao Shanglong
Department of Anaesthesiology, Institute of Anaesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Emergency Medicine, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, China.
Cell Physiol Biochem. 2017;43(3):1140-1151. doi: 10.1159/000481755. Epub 2017 Oct 5.
This study aimed to evaluate the protective effect and mechanisms of remote limb ischaemic postconditioning (RIPostC) against myocardial ischaemia/reperfusion (IR) injury.
Male mice underwent 45 min of coronary artery occlusion followed by 2 h of reperfusion. RIPostC was achieved by three cycles of 5 min of ischaemia and 5 min of reperfusion in the left hind limb at the start of the reperfusion period. After 2 h of cardiac reperfusion, myocardial infarct size, cardiac enzyme release, apoptosis and oxidative stress were assessed. Protein expression and phosphorylation were measured by Western blotting.
RIPostC significantly decreased cardiac IR injury, as reflected by reduced infarct size and cellular apoptosis (22.9 ± 3.3% vs 40.9 ± 6.2% and 13.4% ± 3.1% vs 26.2% ± 3.1%, respectively, both P < 0.01) as well as plasma creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) release (21.97 ± 4.08 vs 35.86 ± 2.91 ng/ml and 6.17 ± 0.58 vs 8.37 ± 0.89 U/ml, respectively, both P < 0.01) compared with the IR group. RIPostC significantly increased the phosphorylation of myocardial STAT3, Akt and eNOS (P < 0.01). In addition, RIPostC elevated the nuclear translocation of Nrf2 and the expression of HO-1 and reduced myocardial oxidative stress (P < 0.05). Interestingly, pretreatment with the JAK/STAT3 inhibitor AG490 blocked the cardioprotective effect of RIPostC accompanied by decreased phosphorylation of myocardial STAT3, Akt and eNOS (P < 0.05), decreased nuclear translocation of Nrf2 and expression of HO-1, as well as increased oxidative stress (P < 0.05).
RIPostC attenuates apoptosis and protects against myocardial IR injury, possibly through the activation of JAK/STAT3-mediated Nrf2-antioxidant signalling.
本研究旨在评估远程肢体缺血后处理（RIPostC）对心肌缺血/再灌注（IR）损伤的保护作用及其机制。
雄性小鼠经历45分钟冠状动脉闭塞，随后进行2小时再灌注。在再灌注期开始时，通过左后肢5分钟缺血和5分钟再灌注的三个循环实现RIPostC。心脏再灌注2小时后，评估心肌梗死面积、心肌酶释放、细胞凋亡和氧化应激。通过蛋白质印迹法测量蛋白质表达和磷酸化水平。
RIPostC显著降低心脏IR损伤，表现为梗死面积减小和细胞凋亡减少（分别为22.9±3.3%对40.9±6.2%和13.4%±3.1%对26.2%±3.1%，均P<0.01），以及血浆肌酸激酶-MB（CK-MB）和乳酸脱氢酶（LDH）释放减少（分别为21.97±4.08对35.86±2.91 ng/ml和6.17±0.58对8.37±0.89 U/ml，均P<0.01），与IR组相比。RIPostC显著增加心肌STAT3、Akt和eNOS的磷酸化水平（P<0.01）。此外，RIPostC提高了Nrf2的核转位和HO-1的表达，并降低了心肌氧化应激（P<0.05）。有趣的是，用JAK/STAT3抑制剂AG490预处理可阻断RIPostC的心脏保护作用，同时伴有心肌STAT3、Akt和eNOS磷酸化水平降低（P<0.05），Nrf2核转位和HO-1表达减少，以及氧化应激增加（P<0.05）。
RIPostC可减轻细胞凋亡并预防心肌IR损伤，可能是通过激活JAK/STAT3介导的Nrf2-抗氧化信号通路。
