title: Genetic and pharmacological inhibition of Rheb1-mTORC1 signaling exerts cardioprotection against adverse cardiac remodeling in mice.
abstract: A previous study indicated that Rheb1 is required for mammalian target of TOR complex 1 (mTORC1) signaling in the brain. However, the function of Rheb1 in the heart is still elusive. In the present study, we deleted Rheb1 specifically in cardiomyocytes and found that reduced Rheb1 levels conferred cardioprotection against pathologic remodeling in myocardial infarction (MI) and pressure overload (transverse aortic constriction) mouse models. Cardiomyocyte apoptosis was reduced and mTORC1 activity was suppressed in cardiomyocyte Rheb1-deletion mice, suggesting that Rheb1 regulates mTORC1 activation in myocardium. Furthermore, we demonstrated that astragaloside IV (As-IV) could inhibit mTORC1, and As-IV treatment displayed similar protection against MI and transverse aortic constriction as Rheb1 genetic inhibition. This study indicates that Rheb1 is essential for mTORC1 activation in cardiomyocytes and suggests that targeting Rheb1-mTORC1 signaling, such as by As-IV treatment, may be an effective therapeutic method for treating patients with adverse cardiac remodeling after MI and hypertrophy.
authors.affiliation: Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Xiangqi
authors.initials: X
authors.lastname: Wu
authors.forename: Yunshan
authors.initials: Y
authors.lastname: Cao
authors.forename: Junwei
authors.initials: J
authors.lastname: Nie
authors.forename: Hailang
authors.initials: H
authors.lastname: Liu
authors.forename: Shuangshuang
authors.initials: S
authors.lastname: Lu
authors.forename: Xiaoshan
authors.initials: X
authors.lastname: Hu
authors.forename: Jingai
authors.initials: J
authors.lastname: Zhu
authors.forename: Xia
authors.initials: X
authors.lastname: Zhao
authors.forename: Jiandong
authors.initials: J
authors.lastname: Chen
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Chen
authors.forename: Zhongzhou
authors.initials: Z
authors.lastname: Yang
authors.forename: Xinli
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D006332:Cardiomegaly / Q000517:prevention & control; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical / Q000379:methods; D017353:Gene Deletion; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D020559:Monomeric GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D046912:Multiprotein Complexes / Q000378:metabolism*; D009203:Myocardial Infarction / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D009479:Neuropeptides / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D000076205:Ras Homolog Enriched in Brain Protein; D012503:Saponins / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014315:Triterpenes / Q000494:pharmacology / Q000627:therapeutic use; D020257:Ventricular Remodeling / Q000187:drug effects / Q000502:physiology*
chemical_list: D002316:Cardiotonic Agents; D046912:Multiprotein Complexes; D009479:Neuropeptides; D000076205:Ras Homolog Enriched in Brain Protein; C490213:Rheb protein, mouse; D012503:Saponins; D014315:Triterpenes; C052064:astragaloside A; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins