鸢尾素对缺血再灌注心肌铁死亡的抑制作用  

Irisin alleviates myocardial ischemia-reperfusion injury by inhibiting ferroptosis

作　　者：李丽 于昊祯 王一石 殷玥 余璐 仝武军 LI Li;YU Hao-zhen;WANG Yi-shi;YIN Yue;YU Lu;TONG Wu-jun(Department of Pharmacy PLA Lintong Sanitarium,Xi'an 710600,Shaanxi,China;School of Basic Medical Sciences,Shaanxi University of Chinese Medicine,Xianyang 712046,Shaanxi,China;Department of Pathology,School of Basic Medical Sciences,Air Force Medical University,Xi'an 710032,Shaanxi,China)

机构地区：[1]联勤保障部队临潼康复疗养中心药剂科,陕西西安710600 [2]陕西中医药大学基础医学院,陕西咸阳712046 [3]空军军医大学基础医学院病理学教研室,陕西西安710032

出　　处：《心脏杂志》2021年第5期465-471,477,共8页Chinese Heart Journal

基　　金：陕西省社发攻关项目资助(2018SF-270)。

摘　　要：目的建立小鼠心肌缺血再灌注(MI/R)损伤模型,探讨鸢尾素(irisin)能否抑制心肌铁死亡进而发挥心肌保护作用。方法将80只5周龄健康雄性C57小鼠随机分为正常对照组(40只)和运动训练组(40只)。运动组完成训练后进一步将两组小鼠分为假手术组和MI/R组(每组20只)。采用小鼠急性MI/R在体模型(缺血30 min,再灌注24 h)于再灌注后取心肌组织,检测各组血清及组织中irisin水平、铁死亡相关信号表达、心肌梗死面积和整体心脏功能。在细胞学实验中,采用H9c2心肌细胞建立缺氧/复氧(H/R)模型并给予irisin处理后检测铁死亡相关信号表达情况。结果铁死亡抑制剂ferrostatin-1可显著减小MI/R心肌梗死面积,降低MI/R心肌中铁死亡标志物Ptgs2 mRNA和丙二醛(MDA)水平,提示心肌铁死亡是MI/R心肌损伤的重要部分。与对照组相比,有氧运动训练可有效提高骨骼肌和心肌中的irisin水平(P<0.05)。运动组MI/R心肌的铁死亡程度被显著抑制,心肌Ptgs2mRNA、MDA和脂质过氧化程度均显著降低(P<0.05),心功能显著改善(P<0.05)。外源性补充irisin可有效提高MI/R心肌中GPX4水平而抑制心肌铁死亡程度,减小心肌梗死面积(P<0.05)。细胞学实验发现采用siRNA抑制H9c2细胞整合素αV/β5受体可有效阻断irisin对铁死亡的抑制作用。结论鸢尾素通过整合素αV/β5受体-GPX4信号途径抑制MI/R心肌铁死亡。有氧运动训练可通过提高内源性irisin水平实现心肌保护作用。AIM To investigate whether Irisin protects against myocardial ischemia/reperfusion(MI/R)induced ferroptosis in mice. METHODS Eighty healthy male C57 mice aged 5 weeks were randomly divided into a normal control group(40 mice) and an exercise training group(40 mice). After the exercise training, the two groups of mice were further divided into sham group and MI/R group(20 in each group).The in vivo mouse models of myocardial I/R injury were used. After 30 min ischemia and 24 h reperfusion period, heart tissues were excised. The levels of irisin in serum and tissues of each group, the expression of iron death-related signals, and the area of myocardial infarction were measured. Myocardial function was also evaluated. In cytology experiments, in vitro hypoxia/reoxygenation(H/R) injury model for H9 C2 cardiomyocytes with irisin treatment were used to detect the expression of ferroptosis-related signals. RESULTS The ferroptosis inhibitor ferrostatin-1(Fer-1) significantly reduced the MI/R myocardial infarction area and decreased the levels of cardiac Ptgs2 mRNA and MDA, suggesting that myocardial ferroptosis was involved in MI/R injury. Compared with the control group, aerobic exercise training effectively increased the level of irisin in skeletal muscle and myocardium(P<0.05). In addition,the degree of myocardial ferroptosis in the exercise MI/R group was significantly inhibited, manifested as myocardial Ptgs2 mRNA, MDA and lipid peroxidation were significantly reduced(P<0.05), while cardiac function was significantly improved(P<0.05). Exogenous supplementation of irisin effectively increased the level of GPX4 in MI/R myocardium, inhibited myocardial ferroptosis, and reduced the area of myocardial infarction(P<0.05). Cytological experiments found that irisin-induced ferroptosis inhibition was effectively blocked by knockdown of integrin αV/β5 receptor using siRNA. CONCLUSION Irisin inhibits MI/R myocardial ferroptosis through the integrin αV/β5-GPX4 signaling pathway. Aerobic exercise training achieves cardioprot

关 键 词：鸢尾素 心肌缺血再灌注损伤 铁死亡 心肌梗死 

分 类 号：R331.3[医药卫生—人体生理学] R339.4[医药卫生—基础医学]