Liver-heart crosstalk controls IL-22 activity in cardiac protection after myocardial infarction.
Liver-heart crosstalk controls IL-22 activity in cardiac protection after myocardial infarction.
复制标题
肝心串扰控制IL-22活性在心肌梗死后的心脏保护中的作用
DOI：
10.7150/thno.24723
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发表时间：
2018
期刊：
影响因子：
12.4
通讯作者：
Cheng X
中科院分区：
文献类型：
--
作者：
Tang TT;Li YY;Li JJ;Wang K;Han Y;Dong WY;Zhu ZF;Xia N;Nie SF;Zhang M;Zeng ZP;Lv BJ;Jiao J;Liu H;Xian ZS;Yang XP;Hu Y;Liao YH;Wang Q;Tu X;Mallat Z;Huang Y;Shi GP;Cheng X
白细胞介素(IL)-22调节组织炎症和修复。在这里，我们报告肝脏在急性心肌梗死（MI）后参与il -22介导的心脏修复。方法：采用左升动脉结扎法诱导小鼠心肌梗死，观察IL-22对心肌梗死后心功能及心室重构的影响。结果：在左冠状动脉前降支结扎诱导心肌梗死后28天，每天皮下注射100µg/kg小鼠重组IL-22 7天，可减轻小鼠不良心室重构，改善心功能。信号转导和转录激活因子（STAT3）的药理抑制可抑制这些IL-22活性。虽然心肌细胞选择性地去除STAT3并不影响IL-22在心肌梗死后心脏损伤保护中的活性，但肝细胞特异性地去除STAT3完全抑制了这些IL-22的心脏保护活性。在给药IL-22后，肝细胞源性成纤维细胞生长因子（FGF21）以stat3依赖的方式显著增加，并解释了IL-22的心脏保护作用。微阵列分析显示，FGF21控制心肌细胞基因的表达，这些基因参与胆固醇稳态、DNA修复、过氧化物酶体、氧化磷酸化、糖酵解、细胞凋亡和类固醇反应，所有这些都与心肌细胞的存活有关。结论：急性心肌梗死后第1周补充IL-22可有效预防左心功能障碍和心力衰竭。在证实肝STAT3-FGF21轴在IL-22诱导心肌梗死后心脏保护中的作用后，IL-22的活性涉及肝脏和心脏之间的串扰。
Interleukin (IL)-22 regulates tissue inflammation and repair. Here we report participation of the liver in IL-22-mediated cardiac repair after acute myocardial infarction (MI). Methods: We induced experimental MI in mice by ligation of the left ascending artery and evaluated the effect of IL-22 on post-MI cardiac function and ventricular remodeling. Results: Daily subcutaneous injection of 100 µg/kg mouse recombinant IL-22 for seven days attenuated adverse ventricular remodeling and improved cardiac function in mice at 28 days after left anterior descending coronary artery ligation-induced MI. Pharmacological inhibition of signal transducer and activator of transcription (STAT3) muted these IL-22 activities. While cardiomyocyte-selective depletion of STAT3 did not affect IL-22 activities in protecting post-MI cardiac injury, hepatocyte-specific depletion of STAT3 fully muted these IL-22 cardioprotective activities. Hepatocyte-derived fibroblast growth factor (FGF21) was markedly increased in a STAT3-dependent manner following IL-22 administration and accounted for the cardioprotective benefit of IL-22. Microarray analyses revealed that FGF21 controlled the expression of cardiomyocyte genes that are involved in cholesterol homeostasis, DNA repair, peroxisome, oxidative phosphorylation, glycolysis, apoptosis, and steroid responses, all of which are responsible for cardiomyocyte survival. Conclusions: Supplementation of IL-22 in the first week after acute MI effectively prevented left ventricular dysfunction and heart failure. This activity of IL-22 involved crosstalk between the liver and heart after demonstrating a role of the hepatic STAT3-FGF21 axis in IL-22-induced post-MI cardiac protection.