Yang Yanfei, Del Re Dominic P, Nakano Noritsugu, Sciarretta Sebastiano, Zhai Peiyong, Park Jiyeon, Sayed Danish, Shirakabe Akihiro, Matsushima Shoji, Park Yongkyu, Tian Bin, Abdellatif Maha, Sadoshima Junichi
From the Cardiovascular Research Institute and the Department of Cell Biology and Molecular Medicine (Y.Y., D.P.D.R., N.N., P.Z., D.S., A.S., S.M., Y.P., M.A., J.S.), and Department of Biochemistry (J.P., B.T.), Rutgers, New Jersey Medical School, Newark; and the Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Latina and IRCCS Neuromed, Pozzilli (IS), Italy (S.S.).
Circ Res. 2015 Oct 23;117(10):891-904. doi: 10.1161/CIRCRESAHA.115.306624. Epub 2015 Sep 2.
In Drosophila, the Hippo signaling pathway negatively regulates organ size by suppressing cell proliferation and survival through the inhibition of Yorkie, a transcriptional cofactor. Yes-associated protein (YAP), the mammalian homolog of Yorkie, promotes cardiomyocyte growth and survival in postnatal hearts. However, the underlying mechanism responsible for the beneficial effect of YAP in cardiomyocytes remains unclear.
We investigated whether miR-206, a microRNA known to promote hypertrophy in skeletal muscle, mediates the effect of YAP on promotion of survival and hypertrophy in cardiomyocytes.
Microarray analysis indicated that YAP increased miR-206 expression in cardiomyocytes. Increased miR-206 expression induced cardiac hypertrophy and inhibited cell death in cultured cardiomyocytes, similar to that of YAP. Downregulation of endogenous miR-206 in cardiomyocytes attenuated YAP-induced cardiac hypertrophy and survival, suggesting that miR-206 plays a critical role in mediating YAP function. Cardiac-specific overexpression of miR-206 in mice induced hypertrophy and protected the heart from ischemia/reperfusion injury, whereas suppression of miR-206 exacerbated ischemia/reperfusion injury and prevented pressure overload-induced cardiac hypertrophy. miR-206 negatively regulates Forkhead box protein P1 expression in cardiomyocytes and overexpression of Forkhead box protein P1 attenuated miR-206-induced cardiac hypertrophy and survival, suggesting that Forkhead box protein P1 is a functional target of miR-206.
YAP increases the abundance of miR-206, which in turn plays an essential role in mediating hypertrophy and survival by silencing Forkhead box protein P1 in cardiomyocytes.
在果蝇中，Hippo信号通路通过抑制转录辅因子Yorkie来抑制细胞增殖和存活，从而对器官大小进行负向调节。Yes相关蛋白（YAP）是Yorkie的哺乳动物同源物，可促进出生后心脏中心肌细胞的生长和存活。然而，YAP在心肌细胞中产生有益作用的潜在机制仍不清楚。
我们研究了已知可促进骨骼肌肥大的微小RNA miR-206是否介导YAP对心肌细胞存活和肥大促进作用的影响。
微阵列分析表明，YAP可增加心肌细胞中miR-206的表达。miR-206表达增加可诱导心脏肥大并抑制培养心肌细胞中的细胞死亡，这与YAP的作用相似。心肌细胞中内源性miR-206的下调减弱了YAP诱导的心脏肥大和存活，表明miR-206在介导YAP功能中起关键作用。小鼠心脏特异性过表达miR-206可诱导肥大并保护心脏免受缺血/再灌注损伤，而抑制miR-206则会加重缺血/再灌注损伤并阻止压力超负荷诱导的心脏肥大。miR-206在心肌细胞中负向调节叉头框蛋白P1的表达，叉头框蛋白P1的过表达减弱了miR-206诱导的心脏肥大和存活，表明叉头框蛋白P1是miR-206的功能靶点。
YAP增加了miR-206的丰度，而miR-206反过来通过沉默心肌细胞中的叉头框蛋白P1在介导肥大和存活中起重要作用。
