Abstract 16610: High Fat Diet-Induced Obesity is Associated With Increased Ischemia Susceptibility Due to Deregulated Activation of the Rheb/mTORC1 Pathway and Inhibition of Autophagy
The mTOR complex 1 (mTORC1) is a sensor of energy deprivation (ED). The mechanism mediating mTORC1 downregulation during ED and the role of the mTORC1 pathway in regulating the cardiomyocyte (CM) response to ED remains unknown. We here demonstrate that mTORC1 is inhibited during glucose deprivation (GD) in vitro, and during acute myocardial ischemia in vivo through inactivation of Rheb, a GTP-binding protein (-31.7% and -33.7% in Rheb-bound GTP, p<0.05). Forced activation of mTORC1, through Rheb overexpression in vitro, and inducible cardiac-specific Rheb overexpression in vivo, reduced CM survival during GD (-42.6 ± 6.0 % at 18 hours, p<0.01), and increased infarct size after ischemia (3 hours, +60 ± 19 %, p<0.05), both of which were accompanied by inhibition of autophagy. Restoration of autophagy by rapamycin (Rap) or Atg7 increased the ATP content and reduced endoplasmic stress, thereby inhibiting cell death induced by mTORC1 activation. Obesity and metabolic syndrome, two highly morbid conditions, are associated with activation of mTORC1. We investigated whether these conditions are associated with increased myocardial ischemia susceptibility due to deregulated activation of the Rheb/mTORC1 pathway. Mice with high fat diet-induced obesity and metabolic syndrome (HFD mice) exhibited activation of Rheb and mTORC1 (135% and 158% of control, p<0.05) in the heart. After prolonged myocardial ischemia, HFD mice presented an increase in infarct size (+54 ± 13 %, p<0.05), and in the number of TUNEL and hairpin-2-positive cells (2.01 and 1.65 fold, p<0.05) with respect to controls. During ischemia, autophagy was inhibited in HFD mice, as evidenced by a significant reduction in LC3 puncta (-47% in Tg-GFP-LC3 mice fed with HFD, p<0.05). Selective inhibition of mTORC1 by Rap restored autophagy and abrogated the increase in infarct size observed in HFD mice (+142% and -48%, p<0.05), but it failed to protect HFD mice in the presence of genetic disruption of autophagy (beclin1+/- mice fed with HFD). Our data suggest that inhibition of the Rheb/mTORC1 pathway during CM energy deprivation is protective through activation of autophagy. Rheb and mTORC1 may represent therapeutic targets to reduce myocardial damage during prolonged myocardial ischemia in obese patients.
- © 2011 by American Heart Association, Inc.