Department of Clinical Pharmacology and Pharmacogenomics, Osaka University, Japan.
Circulation. 2010 Feb 9;121(5):684-91. doi: 10.1161/CIRCULATIONAHA.109.893677. Epub 2010 Jan 25.
Glycoprotein 130 is the common receptor subunit for the interleukin (IL)-6 cytokine family. Previously, we reported that pretreatment of IL-11, an IL-6 family cytokine, activates the glycoprotein 130 signaling pathway in cardiomyocytes and prevents ischemia/reperfusion injury in vivo; however, its long-term effects on cardiac remodeling after myocardial infarction (MI) remain to be elucidated.
MI was generated by ligating the left coronary artery in C57BL/6 mice. Real-time reverse transcription polymerase chain reaction analyses showed that IL-11 mRNA was remarkably upregulated in the hearts exposed to MI. Intravenous injection of IL-11 activated signal transducer and activator of transcription 3 (STAT3), a downstream signaling molecule of glycoprotein 130, in cardiomyocytes in vivo, suggesting that cardiac myocytes are target cells of IL-11 in the hearts. Twenty-four hours after coronary ligation, IL-11 was administered intravenously, followed by consecutive administration every 24 hours for 4 days. IL-11 treatment reduced fibrosis area 14 days after MI, attenuating cardiac dysfunction. Consistent with a previous report that STAT3 exhibits antiapoptotic and angiogenic activity in the heart, IL-11 treatment prevented apoptotic cell death of the bordering myocardium adjacent to the infarct zone and increased capillary density at the border zone. Importantly, cardiac-specific ablation of STAT3 abrogated IL-11-mediated attenuation of fibrosis and was associated with left ventricular enlargement. Moreover, with the use of cardiac-specific transgenic mice expressing constitutively active STAT3, cardiac STAT3 activation was shown to be sufficient to prevent adverse cardiac remodeling.
IL-11 attenuated cardiac fibrosis after MI through STAT3. Activation of the IL-11/glycoprotein 130/STAT3 axis may be a novel therapeutic strategy against cardiovascular diseases.
糖蛋白 130 是白细胞介素（IL）-6 细胞因子家族的共同受体亚基。此前，我们报道过，白细胞介素 11（一种 IL-6 家族细胞因子）预处理可激活心肌细胞中的糖蛋白 130 信号通路，从而防止体内缺血/再灌注损伤；然而，其在心肌梗死后心脏重构的长期影响仍有待阐明。
通过结扎 C57BL/6 小鼠的左冠状动脉来制造心肌梗死。实时逆转录聚合酶链反应分析显示，IL-11mRNA 在暴露于 MI 的心脏中显著上调。体内静脉注射 IL-11 激活了信号转导和转录激活因子 3（STAT3），这是糖蛋白 130 的下游信号分子，表明心肌细胞是心脏中 IL-11 的靶细胞。在冠状动脉结扎后 24 小时，静脉注射 IL-11，然后连续每天注射 4 天，共注射 4 天。IL-11 治疗可减少心肌梗死后 14 天的纤维化面积，从而减轻心脏功能障碍。与之前的报告一致，即 STAT3 在心脏中具有抗凋亡和血管生成活性，IL-11 治疗可防止梗死区边缘心肌的凋亡细胞死亡，并增加边缘区的毛细血管密度。重要的是，STAT3 的心脏特异性消融消除了 IL-11 介导的纤维化减弱作用，并与左心室扩大相关。此外，使用表达组成性激活 STAT3 的心脏特异性转基因小鼠表明，心脏 STAT3 的激活足以预防不良的心脏重构。
IL-11 通过 STAT3 减轻心肌梗死后的心脏纤维化。激活 IL-11/糖蛋白 130/STAT3 轴可能是对抗心血管疾病的一种新的治疗策略。
