title: Rheb is a critical regulator of autophagy during myocardial ischemia: pathophysiological implications in obesity and metabolic syndrome.
abstract: BACKGROUND
  Rheb is a GTP-binding protein that promotes cell survival and mediates the cellular response to energy deprivation (ED). The role of Rheb in the regulation of cell survival during ED has not been investigated in the heart.
  
  
  RESULTS
  Rheb is inactivated during cardiomyocyte (CM) glucose deprivation (GD) in vitro, and during acute myocardial ischemia in vivo. Rheb inhibition causes mTORC1 inhibition, because forced activation of Rheb, through Rheb overexpression in vitro and through inducible cardiac-specific Rheb overexpression in vivo, restored mTORC1 activity. Restoration of mTORC1 activity reduced CM survival during GD and increased infarct size after ischemia, both of which were accompanied by inhibition of autophagy, whereas Rheb knockdown increased autophagy and CM survival. Rheb inhibits autophagy mostly through Atg7 depletion. Restoration of autophagy, through Atg7 reexpression and inhibition of mTORC1, increased cellular ATP content and reduced endoplasmic reticulum stress, thereby reducing CM death induced by Rheb activation. Mice with high-fat diet-induced obesity and metabolic syndrome (HFD mice) exhibited deregulated cardiac activation of Rheb and mTORC1, particularly during ischemia. HFD mice presented inhibition of cardiac autophagy and displayed increased ischemic injury. Pharmacological and genetic inhibition of mTORC1 restored autophagy and abrogated the increase in infarct size observed in HFD mice, but they failed to protect HFD mice in the presence of genetic disruption of autophagy.
  
  
  CONCLUSIONS
  Inactivation of Rheb protects CMs during ED through activation of autophagy. Rheb and mTORC1 may represent therapeutic targets to reduce myocardial damage during ischemia, particularly in obese patients.
authors.affiliation: Cardiovascular Research Institute, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Medical Science Building, Newark, NJ 07103, USA.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Sciarretta
authors.forename: Peiyong
authors.initials: P
authors.lastname: Zhai
authors.forename: Dan
authors.initials: D
authors.lastname: Shao
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Maejima
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Robbins
authors.forename: Massimo
authors.initials: M
authors.lastname: Volpe
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Condorelli
authors.forename: Junichi
authors.initials: J
authors.lastname: Sadoshima
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000502:physiology*; D000071186:Beclin-1; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D004041:Dietary Fats / Q000494:pharmacology; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D004734:Energy Metabolism / Q000502:physiology; D005947:Glucose / Q000494:pharmacology; D024821:Metabolic Syndrome / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000076205:Ras Homolog Enriched in Brain Protein; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D004041:Dietary Fats; D009479:Neuropeptides; D000076205:Ras Homolog Enriched in Brain Protein; C490213:Rheb protein, mouse; C087693:Rheb protein, rat; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins; D005947:Glucose