CITED4 induces physiologic hypertrophy and promotes functional recovery after ischemic injury
CITED4 induces physiologic hypertrophy and promotes functional recovery after ischemic injury
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DOI：
10.1172/jci.insight.85904
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发表时间：
2016-06-16
期刊：
影响因子：
8
通讯作者：
Rosenzweig, Anthony
中科院分区：
文献类型：
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作者：
Bezzerides, Vassilios J.;Platt, Colin;Rosenzweig, Anthony
运动介导其多种心脏益处的机制仅部分了解。先前对运动动态调节的心脏转录组分和microRNA的综合分析表明，CBP/p300相互作用蛋白CITED 4是两个网络中的下游效应子。虽然CITED 4已经记录了体外新生心肌细胞的功能后果，但对其在成人心脏中的作用一无所知。为了研究成年动物心脏CITED 4表达的影响，我们产生了具有调节的心肌细胞特异性CITED 4表达的转基因小鼠。成年小鼠的心脏CITED 4表达足以诱导心脏重量和心肌细胞大小的增加，具有正常的收缩功能，类似于耐力运动训练的效果。在缺血再灌注后，CITED 4的表达并没有改变初始梗死面积，但介导了实质性的功能恢复，同时减少心室扩张和纤维化。CITED 4的强制心脏表达也诱导了缺血性损伤后mTORC 1通路的强烈激活。此外，药理学抑制mTORC 1废除CITED 4的影响，在体外和体内。总之，这些数据确立了CITED 4作为mTOR信号传导的调节剂，其足以在基线诱导生理性肥大并减轻缺血性损伤后的不良心室重塑。
The mechanisms by which exercise mediates its multiple cardiac benefits are only partly understood. Prior comprehensive analyses of the cardiac transcriptional components and microRNAs dynamically regulated by exercise suggest that the CBP/p300-interacting protein CITED4 is a downstream effector in both networks. While CITED4 has documented functional consequences in neonatal cardiomyocytes in vitro, nothing is known about its effects in the adult heart. To investigate the impact of cardiac CITED4 expression in adult animals, we generated transgenic mice with regulated, cardiomyocyte-specific CITED4 expression. Cardiac CITED4 expression in adult mice was sufficient to induce an increase in heart weight and cardiomyocyte size with normal systolic function, similar to the effects of endurance exercise training. After ischemia-reperfusion, CITED4 expression did not change initial infarct size but mediated substantial functional recovery while reducing ventricular dilation and fibrosis. Forced cardiac expression of CITED4 also induced robust activation of the mTORC1 pathway after ischemic injury. Moreover, pharmacological inhibition of mTORC1 abrogated CITED4's effects in vitro and in vivo. Together, these data establish CITED4 as a regulator of mTOR signaling that is sufficient to induce physiologic hypertrophy at baseline and mitigate adverse ventricular remodeling after ischemic injury.