Class of 2015, No. 6 School of Clinical Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
Department of Cardiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
Can J Cardiol. 2019 Apr;35(4):501-510. doi: 10.1016/j.cjca.2018.12.040. Epub 2019 Jan 18.
Remote ischemic postconditioning (RIPostC) could reduce myocardial ischemia/reperfusion injury markedly. However, the mechanism of the protective signal transfer of RIPostC to the heart remains unclear. In this study, we hypothesize that macrophage migration inhibitory factor (MIF) plays an important role in the cardioprotection conferred by RIPostC.
RIPostC was induced by 4 cycles of 5 min ischemia/5 min reperfusion on the lower limbs of rats immediately after myocardial reperfusion. The plasma level of MIF was compared between the RIPostC and reperfusion injury groups. (S,R)-3-(4-hydroxy -phenyl)-4,5-dihydro-5-isoxazoleacetic acid methyl ester (ISO-1) was used as a potent inhibitor of MIF. 2-methoxyestradiol (2ME2), an inhibitor of HIF-1α (hypoxia-inducible factor-1α)，was used as a tool to inhibit the role of HIF-1α.
We found that a significant elevation in the level of plasma MIF occurred when RIPostC was carried out; this elevation could be blocked by femoral occlusion. The cardiac MIF level decreased significantly after RIPostC stimulus compared with the ischemia/reperfusion (IR) group (P < 0.01). In addition, inhibition of MIF by ISO-1 could induce the loss of cardioprotection and aggravate the apoptosis of the heart in RIPostC. RIPostC confers protection against myocardial IR injury via the MIF-AMPK signaling pathway. Finally, inhibition of HIF-1α may result in the reduction of plasma MIF in RIPostC.
MIF plays an important role in RIPostC through the humoral pathway in a HIF-1α-dependent manner, which could activate the cardiac AMP-activated protein kinase (AMPK) pathway to confer powerful cardioprotection.
远程缺血后处理（RIPostC）可显著减轻心肌缺血/再灌注损伤。然而，RIPostC 对心脏的保护信号转导机制尚不清楚。在这项研究中，我们假设巨噬细胞移动抑制因子（MIF）在 RIPostC 赋予的心脏保护中起重要作用。
在心肌再灌注后立即对大鼠下肢进行 4 个周期的 5 分钟缺血/5 分钟再灌注，以诱导 RIPostC。比较 RIPostC 与再灌注损伤组之间的血浆 MIF 水平。（S，R）-3-（4-羟基-苯基）-4,5-二氢-5-异恶唑乙酸甲酯（ISO-1）被用作 MIF 的有效抑制剂。2-甲氧基雌二醇（2ME2），一种缺氧诱导因子-1α（HIF-1α）的抑制剂，被用作抑制 HIF-1α 作用的工具。
我们发现，当进行 RIPostC 时，血浆 MIF 水平显著升高；这种升高可以通过股动脉闭塞来阻断。与缺血/再灌注（IR）组相比，RIPostC 刺激后心脏 MIF 水平显著降低（P < 0.01）。此外，通过 ISO-1 抑制 MIF 可导致 RIPostC 中的心脏保护丧失并加重心脏细胞凋亡。RIPostC 通过 MIF-AMPK 信号通路对心肌 IR 损伤提供保护。最后，抑制 HIF-1α 可能导致 RIPostC 中血浆 MIF 的减少。
MIF 通过 HIF-1α 依赖性的体液途径在 RIPostC 中起重要作用，可激活心脏 AMP 激活蛋白激酶（AMPK）通路，从而提供强大的心脏保护作用。
