Expression cloning of cardiotrophin 1, a cytokine that induces cardiac myocyte hypertrophy.

Heart failure continues to be a leading cause of mortality worldwide. A hallmark of this disease is dilated cardiac hypertrophy, which is accompanied by a reactivation of genes expressed in fetal heart development. Reasoning that fetal or embryonic growth factors may mediate the onset of cardiac hypertrophy, we have coupled expression cloning with an embryonic stem cell-based model of cardiogenesis to isolate a 21.5-kDa protein, cardiotrophin 1, that potently induces cardiac myocyte hypertrophy in vitro. Amino acid similarity data indicate that cardiotrophin 1 is a member of the leukemia inhibitory factor/ciliary neurotrophic factor/oncostatin M/interleukin 6/interleukin 11 family of cytokines. Several members of this family that are known to signal through the transmembrane protein gp130 stimulate cardiac myocyte hypertrophy, like cardiotrophin 1, suggesting that the gp130 signaling pathway may play a role in cardiac hypertrophy. A 1.4-kb cardiotrophin 1 mRNA is expressed in the heart and several other mouse tissues. IMAGES:

心力衰竭仍是全球范围内的主要致死病因。该疾病的标志性病理特征为扩张性心肌肥厚，伴随胎儿心脏发育阶段表达的基因发生重激活。基于胎儿或胚胎生长因子可能介导心肌肥厚发生的推论，我们将表达克隆技术与基于胚胎干细胞的心脏发生模型相结合，成功分离得到一种分子量为21.5kDa的蛋白质——心肌营养素1（cardiotrophin 1），该蛋白可在体外强效诱导心肌细胞肥厚。氨基酸序列相似性分析数据表明，心肌营养素1属于白血病抑制因子/睫状神经营养因子/抑瘤素M/白细胞介素6/白细胞介素11细胞因子家族。该家族中多个已知通过跨膜蛋白gp130进行信号转导的成员，均可如心肌营养素1一般刺激心肌细胞肥厚，这提示gp130信号通路可能在心肌肥厚的发生发展中发挥作用。在小鼠的心脏及其他多种组织中，均可检测到1.4kb的心肌营养素1 mRNA的表达。图片：