title: Cardioprotective Signature of Short-Term Caloric Restriction.
abstract: OBJECTIVE
  To understand the molecular pathways underlying the cardiac preconditioning effect of short-term caloric restriction (CR).
  
  
  BACKGROUND
  Lifelong CR has been suggested to reduce the incidence of cardiovascular disease through a variety of mechanisms. However, prolonged adherence to a CR life-style is difficult. Here we reveal the pathways that are modulated by short-term CR, which are associated with protection of the mouse heart from ischemia.
  
  
  METHODS
  Male 10-12 wk old C57bl/6 mice were randomly assigned to an ad libitum (AL) diet with free access to regular chow, or CR, receiving 30% less food for 7 days (d), prior to myocardial infarction (MI) via permanent coronary ligation. At d8, the left ventricles (LV) of AL and CR mice were collected for Western blot, mRNA and microRNA (miR) analyses to identify cardioprotective gene expression signatures. In separate groups, infarct size, cardiac hemodynamics and protein abundance of caspase 3 was measured at d2 post-MI.
  
  
  RESULTS
  This short-term model of CR was associated with cardio-protection, as evidenced by decreased infarct size (18.5±2.4% vs. 26.6±1.7%, N=10/group; P=0.01). mRNA and miR profiles pre-MI (N=5/group) identified genes modulated by short-term CR to be associated with circadian clock, oxidative stress, immune function, apoptosis, metabolism, angiogenesis, cytoskeleton and extracellular matrix (ECM). Western blots pre-MI revealed CR-associated increases in phosphorylated Akt and GSK3ß, reduced levels of phosphorylated AMPK and mitochondrial related proteins PGC-1α, cytochrome C and cyclooxygenase (COX) IV, with no differences in the levels of phosphorylated eNOS or MAPK (ERK1/2; p38). CR regimen was also associated with reduced protein abundance of cleaved caspase 3 in the infarcted heart and improved cardiac function.
authors.affiliation: Division of Experimental Therapeutics, Toronto General Research Institute, Toronto, Ontario, Canada.
authors.forename: Hossein
authors.initials: H
authors.lastname: Noyan
authors.affiliation: Division of Experimental Therapeutics, Toronto General Research Institute, Toronto, Ontario, Canada.
authors.forename: Omar
authors.initials: O
authors.lastname: El-Mounayri
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ruth
authors.initials: R
authors.lastname: Isserlin
authors.affiliation: Division of Experimental Therapeutics, Toronto General Research Institute, Toronto, Ontario, Canada.
authors.forename: Sara
authors.initials: S
authors.lastname: Arab
authors.affiliation: Division of Experimental Therapeutics, Toronto General Research Institute, Toronto, Ontario, Canada.
authors.forename: Abdul
authors.initials: A
authors.lastname: Momen
authors.affiliation: Division of Advanced Diagnostics, Toronto General Research Institute, Toronto, Ontario Canada.
authors.forename: Henry S
authors.initials: HS
authors.lastname: Cheng
authors.affiliation: Division of Advanced Diagnostics, Toronto General Research Institute, Toronto, Ontario Canada.
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.affiliation: Division of Experimental Therapeutics, Toronto General Research Institute, Toronto, Ontario, Canada.
authors.forename: Talat
authors.initials: T
authors.lastname: Afroze
authors.affiliation: Division of Advanced Diagnostics, Toronto General Research Institute, Toronto, Ontario Canada; Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, University of Toronto, Toronto, Ontario, Canada; Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Ren-Ke
authors.initials: RK
authors.lastname: Li
authors.affiliation: Division of Advanced Diagnostics, Toronto General Research Institute, Toronto, Ontario Canada; Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada; Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, University of Toronto, Toronto, Ontario, Canada; Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Fish
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada; The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Bader
authors.affiliation: Division of Experimental Therapeutics, Toronto General Research Institute, Toronto, Ontario, Canada; Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada; Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, University of Toronto, Toronto, Ontario, Canada; Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Ted Rogers Centre for Heart Research, University Health Network, Toronto, Ontario, Canada.
authors.forename: Mansoor
authors.initials: M
authors.lastname: Husain
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D031204:Caloric Restriction; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; D045304:Cytochromes c; D052250:Nitric Oxide Synthase Type III; D011451:Prostaglandin-Endoperoxide Synthases; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D055372:AMP-Activated Protein Kinases