南方医科大学学报

南方医科大学学报 ›› 2021, Vol. 41 ›› Issue (8): 1165-1170.doi: 10.12122/j.issn.1673-4254.2021.08.06

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褪黑素通过激活Nrf2信号和抑制炎症反应减轻小鼠心脏缺血再灌注损伤

孔令恒，徐臣年，孙 娜，梁 飞，魏 明，苏兴利   

  1. 西安医学院基础部基础医学研究所，药学院，陕西 西安 710021；北部战区总医院心血管外科，辽宁 沈阳 110016
  • 出版日期:2021-08-20 发布日期:2021-09-07

Melatonin alleviates myocardial ischemia-reperfusion injury in mice by inhibiting inflammatory response via activating Nrf2 signaling

KONG Lingheng, XU Chennian, SUN Na, LIANG Fei, WEI Ming, SU Xingli   

  1. Institute of Basic Medical Science, School of Pharmacy, Xi'an Medical University, Xi'an 710021, China; Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, Shenyang 110016, China
  • Online:2021-08-20 Published:2021-09-07

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摘要： 目的 探讨褪黑素（Mel）激活Nrf2信号抑制炎症反应改善小鼠心脏缺血再灌注（IR）损伤的作用。方法 采用小鼠冠状动脉左前降支结扎，缺血30 min，再灌注2 h或24 h模拟缺血再灌注模型，采用随机数字表法将C57/bl6小鼠随机分为4组：假手术组（Sham）、缺血再灌注组（IR）、褪黑素处理缺血再灌注组（Mel+IR）和褪黑素联合Nrf2抑制剂ML-385处理缺血再灌注组（Mel+ML-385+IR）。伊文氏蓝/TTC染色检测心肌梗死面积，ELISA检测血清中LDH含量，超声评价心脏功能，Western blot检测Bax、Bcl2、Nrf2及其底物NQO-1和HO-1以及炎症分子TNF-α、IL-1β、IL-6的表达，TUNEL染色观察细胞凋亡率。结果 和Sham组相比，IR组心肌梗死面积和血清中LDH含量明显增加，心脏功能降低，Bax表达增加而Bcl2表达减少，细胞凋亡率增加，TNF-α、IL-1β、IL-6的表达显著增加（P<0.01），同时，Nrf2、NQO-1、HO-1的表达明显降低（P<0.01）；而给予Mel处理后，可显著减小心肌梗死面积，降低血清中LDH含量，改善心脏功能，减少Bax表达并增加Bcl2表达，减小细胞凋亡率，降低TNF-α、IL-1β、IL-6表达（P<0.01），上调Nrf2、NQO-1和HO-1的表达（P<0.01）；然而，ML-385可明显阻断Mel对心肌缺血再灌注的保护作用和对Nrf2信号的调控。结论 Mel改善小鼠心脏缺血再灌注损伤，其机制与激活Nrf2信号，降低炎症反应有关。

关键词: 褪黑素；Nrf2；炎症反应；缺血再灌注损伤

Abstract: Objective To investigate the protective effect of melatonin against myocardial ischemia- reperfusion (IR) injury in mice and the role of Nrf2 signaling in mediating this effect. Methods C57/bl6 mice were randomized into sham- operated group (Sham), IR group (IR), IR with melatonin treatment (melatonin+IR) group, and IR with melatonin and Nrf2 inhibitor ML-385 (melatonin+ML-385+IR) group. In the latter 3 groups, mouse models of myocardial IR injury were established by ligation of the left anterior descending coronary artery. The infarct size was measured with Evans blue/TTC staining, and serum LDH level was detected using ELISA. The ejection fraction (EF) and fractional shortening (FS) of the mice were measured using Vevo software. The expressions of Bcl2, Bax, Nrf2, Nrf2 substrates NQO-1 and HO-1, TNF-α, IL-1β, and IL-6 in the myocardial tissues were detected with Western blotting. Results Compared with the sham-operated mice, the mouse models of myocardial IR injury showed significantly increased infarct size and serum LDH levels (P<0.01) with obviously decreased EF and FS (P<0.01). The mouse models also showed significantly increased expressions of Bax, TNF-α, IL-1β and IL-6, decreased expression of Bcl2, Nrf2, NQO-1, and HO-1, and increased apoptotic index and TNF-α expression in the myocardial tissue (P< 0.01). Melatonin treatment significantly decreased the infarct size, serum LDH levels, the expressions of Bax, TNF-α, IL-1β and IL-6 (P<0.01), lowered the apoptotic index, and increased the expressions of Bcl2, Nrf2, NQO-1, and HO-1 in the mouse models (P<0.01). The effects of melatonin were obviously blocked by ML-385 treatment in the mouse models. Conclusion Melatonin can alleviate myocardial IR injury in mice by inhibiting inflammatory response via activation of Nrf2 signaling.

Key words: melatonin; Nrf2; inflammatory response; ischemia reperfusion injury