title: Acute, delayed and chronic remote ischemic conditioning is associated with downregulation of mTOR and enhanced autophagy signaling.
abstract: BACKGROUND
  Remote ischemic conditioning (RIC), induced by brief periods of limb ischemia has been shown to decrease acute myocardial injury and chronic responses after acute coronary syndromes. While several signaling pathways have been implicated, our understanding of the cardioprotection and its underlying mediators and mechanisms remains incomplete. In this study we examine the effect of RIC on pro-autophagy signaling as a possible mechanism of benefit.
  
  
  RESULTS
  We examined the role of autophagy in the acute/first window (15 minutes after RIC), delayed/second window (24 hours after RIC) and chronic (24 hours after 9 days of repeated RIC) phases of cardioprotection. C57BL/6 mice (N = 69) were allocated to each treatment phase and further stratified to receive RIC, induced by four cycles of 5 minutes of limb ischemia followed by 5 minutes of reperfusion, or control treatment consisting solely of handling without transient ischemia. The groups included, group 1 (1W control), group 2 (1W RIC), group 3 (2W control), group 4 (2W RIC), group 5 (3W control) and group 6 (3W RIC). Hearts were isolated for assessment of cardiac function and infarct size after global ischemia using a Langendorff preparation. Infarct size was reduced in all three phases of cardioprotection, in association with improvements in post-ischemic left ventricular end diastolic pressure (LVEDP) and developed pressure (LVDP) (P<0.05). The pattern of autophagy signaling varied; 1W RIC increased AMPK levels and decreased the activation of mammalian target of rapamycin (mTOR), whereas chronic RIC was associated with persistent mTOR suppression and increased levels of autophagosome proteins, LC3II/I and Atg5.
  
  
  CONCLUSIONS
  Cardioprotection following transient ischemia exists in both the acute and delayed/chronic phases of conditioning. RIC induces pro-autophagy signaling but the pattern of responses varies depending on the phase, with the most complete portfolio of responses observed when RIC is administered chronically.
authors.affiliation: Division of Cardiology, Labatt Family Heart Center, Hospital for Sick Children, University of Toronto, Ontario, Canada.
authors.forename: Sagar
authors.initials: S
authors.lastname: Rohailla
authors.affiliation: Division of Cardiology, Labatt Family Heart Center, Hospital for Sick Children, University of Toronto, Ontario, Canada.
authors.forename: Nadia
authors.initials: N
authors.lastname: Clarizia
authors.affiliation: Division of Cardiology, Labatt Family Heart Center, Hospital for Sick Children, University of Toronto, Ontario, Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Sourour
authors.affiliation: Division of Cardiology, Labatt Family Heart Center, Hospital for Sick Children, University of Toronto, Ontario, Canada.
authors.forename: Wesam
authors.initials: W
authors.lastname: Sourour
authors.affiliation: Division of Cardiology, Labatt Family Heart Center, Hospital for Sick Children, University of Toronto, Ontario, Canada.
authors.forename: Nitai
authors.initials: N
authors.lastname: Gelber
authors.affiliation: Division of Cardiology, Labatt Family Heart Center, Hospital for Sick Children, University of Toronto, Ontario, Canada.
authors.forename: Can
authors.initials: C
authors.lastname: Wei
authors.affiliation: Division of Cardiology, Labatt Family Heart Center, Hospital for Sick Children, University of Toronto, Ontario, Canada.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Division of Cardiology, Labatt Family Heart Center, Hospital for Sick Children, University of Toronto, Ontario, Canada.
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Redington
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D015536:Down-Regulation; D005121:Extremities / Q000098:blood supply; D019194:Ischemic Preconditioning / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases