Chen Fan, Chen Dandan, Zhang Yubin, Jin Liang, Zhang Han, Wan Miyang, Pan Tianshu, Wang Xiaochuan, Su Yuheng, Xu Yitao, Ye Junmei
State Key Laboratory of Natural Medicines, Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210006, China.
State Key Laboratory of Natural Medicines, Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210006, China; Strathclyde Institute of Pharmacy & Biomedical Sciences, University of Strathclyde, Glasgow, G4 0RE, UK.
Biochem Biophys Res Commun. 2017 Dec 16;494(3-4):534-541. doi: 10.1016/j.bbrc.2017.10.119. Epub 2017 Oct 25.
Interleukin-6 (IL-6) signaling is critical for cardiomyocyte hypertrophy, while the role of IL-6 in the pathogenesis of myocardium hypertrophy remains controversial. To determine the essential role of IL-6 signaling for the cardiac development during AngII-induced hypertension, and to elucidate the mechanisms, wild-type (WT) and IL-6 knockout (IL-6 KO) mice were infused subcutaneously with either vehicle or AngII (1.5 μg/h/mouse) for 1 week. Immunohistological and serum studies revealed that the extents of cardiac fibrosis, inflammation and apoptosis were reduced in IL-6 KO heart during AngII-stimulation, while cardiac hypertrophy was obviously induced. To investigate the underlying mechanisms, by using myocardial tissue and neonatal cardiomyocytes, we observed that IL-6/STAT3 signaling was activated under the stimulation of AngII both in vivo and in vitro. Further investigation suggested that STAT3 activation enhances the inhibitory effect of EndoG on MEF2A and hampers cardiomyocyte hypertrophy. Our study is the first to show the important role of IL-6 in regulating cardiac pathogenesis via inflammation and apoptosis during AngII-induced hypertension. We also provide a novel link between IL-6/STAT3 and EndoG/MEF2A pathway that affects cardiac hypertrophy during AngII stimulation.
白细胞介素-6（IL-6）信号传导对心肌细胞肥大至关重要，而IL-6在心肌肥大发病机制中的作用仍存在争议。为了确定IL-6信号传导在血管紧张素II（AngII）诱导的高血压期间对心脏发育的重要作用，并阐明其机制，将野生型（WT）和IL-6基因敲除（IL-6 KO）小鼠皮下注射载体或AngII（1.5μg/小时/小鼠）1周。免疫组织学和血清学研究表明，在AngII刺激期间，IL-6 KO心脏中的心脏纤维化、炎症和凋亡程度降低，而明显诱导了心脏肥大。为了研究潜在机制，通过使用心肌组织和新生心肌细胞，我们观察到在体内和体外，AngII刺激下IL-6/信号转导和转录激活因子3（STAT3）信号传导均被激活。进一步研究表明，STAT3激活增强了内源性核酸内切酶G（EndoG）对心肌增强因子2A（MEF2A）的抑制作用，并阻碍心肌细胞肥大。我们的研究首次表明IL-6在AngII诱导的高血压期间通过炎症和凋亡调节心脏发病机制中的重要作用。我们还提供了IL-6/STAT3与EndoG/MEF2A途径之间的新联系，该途径在AngII刺激期间影响心脏肥大。
