Cardiac ablation of Rheb1 induces impaired heart growth, endoplasmic reticulum-associated apoptosis and heart failure in infant mice

• Published in: International journal of molecular sciences Vol. 14; no. 12; pp. 24380 - 24398
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 13-12-2013; Molecular Diversity Preservation International (MDPI)
• Subjects: Ablation; Animals; Animals, Newborn; Apoptosis; Arrhythmias, Cardiac - etiology; Arrhythmias, Cardiac - metabolism; Arrhythmias, Cardiac - pathology; Cardiac arrhythmia; Cardiomyocytes; Cells, Cultured; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Heart - growth & development; Heart - physiopathology; Heart failure; Heart Failure - etiology; Heart Failure - metabolism; Heart Failure - pathology; heart growth; infant heart failure; JNK Mitogen-Activated Protein Kinases - metabolism; Kinases; Life sciences; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Monomeric GTP-Binding Proteins - deficiency; Monomeric GTP-Binding Proteins - genetics; Monomeric GTP-Binding Proteins - metabolism; mTORC1; Myocytes, Cardiac - cytology; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Neuropeptides - deficiency; Neuropeptides - genetics; Neuropeptides - metabolism; Peptides; Phosphatase; Phosphoric Monoester Hydrolases - metabolism; Phosphorylation; Proteins; Proto-Oncogene Proteins c-akt - metabolism; PTEN Phosphohydrolase - metabolism; Ras Homolog Enriched in Brain Protein; Rheb1; Survival analysis; China
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms141224380

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.