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Cardiac Ablation of Rheb1 Induces Impaired Heart Growth, Endoplasmic Reticulum-Associated Apoptosis and Heart Failure in Infant Mice
Department of Cardiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China
MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061, China
Regeneration Lab and Experimental Center of Life sciences, School of Life Sciences, Shanghai University, Shanghai 200444, China
The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
* Authors to whom correspondence should be addressed.
Received: 22 September 2013; in revised form: 25 November 2013 / Accepted: 3 December 2013 / Published: 13 December 2013
Abstract: 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.
Keywords: Rheb1; heart growth; infant heart failure; mTORC1; ER
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MDPI and ACS Style
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. Cardiac Ablation of Rheb1 Induces Impaired Heart Growth, Endoplasmic Reticulum-Associated Apoptosis and Heart Failure in Infant Mice. Int. J. Mol. Sci. 2013, 14, 24380-24398.
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. Cardiac Ablation of Rheb1 Induces Impaired Heart Growth, Endoplasmic Reticulum-Associated Apoptosis and Heart Failure in Infant Mice. International Journal of Molecular Sciences. 2013; 14(12):24380-24398.
Cao, Yunshan; Tao, Lichan; Shen, Shutong; Xiao, Junjie; Wu, Hang; Li, Beibei; Wu, Xiangqi; Luo, Wen; Xiao, Qi; Hu, Xiaoshan; Liu, Hailang; Nie, Junwei; Lu, Shuangshuang; Yuan, Baiyin; Han, Zhonglin; Xiao, Bo; Yang, Zhongzhou; Li, Xinli. 2013. "Cardiac Ablation of Rheb1 Induces Impaired Heart Growth, Endoplasmic Reticulum-Associated Apoptosis and Heart Failure in Infant Mice." Int. J. Mol. Sci. 14, no. 12: 24380-24398.