TY - JOUR
T1 - Cardiac ablation of Rheb1 induces impaired heart growth, endoplasmic reticulum-associated apoptosis and heart failure in infant mice
AU - Cao, Yunshan
AU - Tao, Lichan
AU - Shen, Shutong
AU - Xiao, Junjie
AU - Wu, Hang
AU - Li, Beibei
AU - Wu, Xiangqi
AU - Luo, Wen
AU - Xiao, Qi
AU - Hu, Xiaoshan
AU - Liu, Hailang
AU - Nie, Junwei
AU - Lu, Shuangshuang
AU - Yuan, Baiyin
AU - Han, Zhonglin
AU - Xiao, Bo
AU - Yang, Zhongzhou
AU - Li, Xinli
PY - 2013/12/13
Y1 - 2013/12/13
N2 - 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.
AB - 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.
KW - ER
KW - Heart growth
KW - Infant heart failure
KW - MTORC1
KW - Rheb1
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U2 - 10.3390/ijms141224380
DO - 10.3390/ijms141224380
M3 - Article
C2 - 24351823
AN - SCOPUS:84890380098
SN - 1661-6596
VL - 14
SP - 24380
EP - 24398
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 12
ER -