New Role for Interleukin-13 Receptor α1 in Myocardial Homeostasis and Heart Failure.
New Role for Interleukin-13 Receptor α1 in Myocardial Homeostasis and Heart Failure.
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DOI：
10.1161/jaha.116.005108
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发表时间：
2017-05-20
影响因子：
5.4
通讯作者：
Leor J
中科院分区：
文献类型：
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作者：
Amit U;Kain D;Wagner A;Sahu A;Nevo-Caspi Y;Gonen N;Molotski N;Konfino T;Landa N;Naftali-Shani N;Blum G;Merquiol E;Karo-Atar D;Kanfi Y;Paret G;Munitz A;Cohen HY;Ruppin E;Hannenhalli S;Leor J
免疫系统在心肌稳态和对损伤的反应中起着关键作用。白细胞介素4和白细胞介素13是抗炎2型细胞因子，通过共同的白细胞介素13受体α1链和2型白细胞介素4受体进行信号传导。白细胞介素-13受体α1在心脏中的作用尚不清楚。我们分析了来自人类供体（n=136）和终末期心力衰竭患者（n=177）的心肌样本。我们发现，白细胞介素-13受体α1存在于心肌中，与互补的2型白细胞介素-4受体链Il 4 ra一起，在心力衰竭患者的心脏中显著下调。接下来，我们发现，与野生型小鼠相比，Il 13 ra 1缺陷小鼠发生严重的心肌功能障碍和不同步（左心室射血分数29.7±9.9 vs 45.0±8.0; P=0.004，左心室舒张末期直径4.2±0.2 vs 3.92±0.3; P=0.03）。对小鼠心脏的生物信息学分析表明，白细胞介素-13受体α1调节心脏中除免疫系统以外的关键途径，如细胞外基质（标准化富集分数=1.90;错误发现率q=0.005）和葡萄糖代谢（标准化富集分数=-2.36;错误发现率q=0）。在正常和压力超负荷条件下，Il 13 ra 1缺乏与胶原沉积减少相关。我们在人类和小鼠中的研究结果首次表明，白细胞介素-13受体α1在心肌稳态和心力衰竭中的作用，并提出了治疗心脏病的新治疗靶点。
The immune system plays a pivotal role in myocardial homeostasis and response to injury. Interleukins‐4 and ‐13 are anti‐inflammatory type‐2 cytokines, signaling via the common interleukin‐13 receptor α1 chain and the type‐2 interleukin‐4 receptor. The role of interleukin‐13 receptor α1 in the heart is unknown. We analyzed myocardial samples from human donors (n=136) and patients with end‐stage heart failure (n=177). We found that the interleukin‐13 receptor α1 is present in the myocardium and, together with the complementary type‐2 interleukin‐4 receptor chain Il4ra, is significantly downregulated in the hearts of patients with heart failure. Next, we showed that Il13ra1‐deficient mice develop severe myocardial dysfunction and dyssynchrony compared to wild‐type mice (left ventricular ejection fraction 29.7±9.9 versus 45.0±8.0; P=0.004, left ventricular end‐diastolic diameter 4.2±0.2 versus 3.92±0.3; P=0.03). A bioinformatic analysis of mouse hearts indicated that interleukin‐13 receptor α1 regulates critical pathways in the heart other than the immune system, such as extracellular matrix (normalized enrichment score=1.90; false discovery rate q=0.005) and glucose metabolism (normalized enrichment score=−2.36; false discovery rate q=0). Deficiency of Il13ra1 was associated with reduced collagen deposition under normal and pressure‐overload conditions. The results of our studies in humans and mice indicate, for the first time, a role of interleukin‐13 receptor α1 in myocardial homeostasis and heart failure and suggests a new therapeutic target to treat heart disease.