Cardiac ablation of Rheb1 induces impaired heart growth, endoplasmic reticulum-associated apoptosis and heart failure in infant mice.
Cardiac ablation of Rheb1 induces impaired heart growth, endoplasmic reticulum-associated apoptosis and heart failure in infant mice.
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DOI：
10.3390/ijms141224380
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发表时间：
2013-12-13
影响因子：
5.6
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
Cao Y;Tao L;Shen S;Xiao J;Wu H;Li B;Wu X;Luo W;Xiao Q;Hu X;Liu H;Nie J;Lu S;Yuan B;Han Z;Xiao B;Yang Z;Li X
Ras同系物Rheb 1在多种细胞过程中起着重要作用。在这项研究中，我们调查Rheb 1在出生后心脏中的作用。我们发现，从出生后小鼠的心肌细胞中删除负责产生Rheb 1的基因会导致这些小鼠的恶性心律失常、心力衰竭和过早死亡。此外，在心力衰竭和心律失常发生之前，在Rheb 1基因敲除小鼠中观察到心脏生长障碍、代谢相关基因表达异常和心肌细胞凋亡增加。此外，蛋白激酶B（PKB/Akt）信号在Rheb 1基因敲除小鼠中增强，去除磷酸酶和张力蛋白同源物（Pten）显著延长Rheb 1基因敲除小鼠的存活时间。此外，Rheb 1突变小鼠中，通过雷帕霉素复合物1（mTORC 1）的哺乳动物靶点的信号传导被消除，C/EBP同源蛋白（CHOP）和c-Jun N-末端激酶（JNK）的磷酸化水平增加。总之，这项研究表明，Rheb 1是重要的，通过调节mTORC 1的活性和内质网的压力，维持出生后的小鼠的心脏功能。此外，Akt信号的激活有助于改善患有晚期心力衰竭的小鼠的存活率。因此，这项研究提供了直接证据，证明Rheb 1在出生后小鼠的心脏中执行多种重要功能。增强Akt活性可提高晚期心力衰竭幼鼠的存活率
Ras homologue enriched in brain 1 (Rheb1) plays an important role in a variety of cellular processes. In this study, we investigate the role of Rheb1 in the post-natal heart. We found that deletion of the gene responsible for production of Rheb1 from cardiomyocytes of post-natal mice resulted in malignant arrhythmias, heart failure, and premature death of these mice. In addition, heart growth impairment, aberrant metabolism relative gene expression, and increased cardiomyocyte apoptosis were observed in Rheb1-knockout mice prior to the development of heart failure and arrhythmias. Also, protein kinase B (PKB/Akt) signaling was enhanced in Rheb1-knockout mice, and removal of phosphatase and tensin homolog (Pten) significantly prolonged the survival of Rheb1-knockouts. Furthermore, signaling via the mammalian target of rapamycin complex 1 (mTORC1) was abolished and C/EBP homologous protein (CHOP) and phosphorylation levels of c-Jun N-terminal kinase (JNK) were increased in Rheb1 mutant mice. In conclusion, this study demonstrates that Rheb1 is important for maintaining cardiac function in post-natal mice via regulation of mTORC1 activity and stress on the endoplasmic reticulum. Moreover, activation of Akt signaling helps to improve the survival of mice with advanced heart failure. Thus, this study provides direct evidence that Rheb1 performs multiple important functions in the heart of the post-natal mouse. Enhancing Akt activity improves the survival of infant mice with advanced heart failure.
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影响因子：
7.2
作者：
Martinez, Juan A.;Zhang, Zhiqun;Larner, Stephen F.
通讯作者：
Larner, Stephen F.
影响因子：
2.3
作者：
Guo, Feng-Jin;Liu, Yanna;Liu, Chuanju
通讯作者：
Liu, Chuanju
影响因子：
--
作者：
Sari, Flori R.;Widyantoro, Bambang;Watanabe, Kenichi
通讯作者：
Watanabe, Kenichi
DOI：
10.1083/jcb.200408161
发表时间：
2004-11-08
期刊：
The Journal of cell biology
影响因子：
--
作者：
Manning BD
通讯作者：
Manning BD
影响因子：
15.9
作者：
Nagoshi, T;Matsui, T;Rosenzweig, A
通讯作者：
Rosenzweig, A