title: Short communication: ischemia/reperfusion tolerance is time-of-day-dependent: mediation by the cardiomyocyte circadian clock.
abstract: BACKGROUND
  Cardiovascular physiology and pathophysiology vary dramatically over the course of the day. For example, myocardial infarction onset occurs with greater incidence during the early morning hours in humans. However, whether myocardial infarction tolerance exhibits a time-of-day dependence is unknown.
  
  
  OBJECTIVE
  To investigate whether time of day of an ischemic insult influences clinically relevant outcomes in mice.
  
  
  RESULTS
  Wild-type mice were subjected to ischemia/reperfusion (I/R) (45 minutes of ischemia followed by 1 day or 1 month of reperfusion) at distinct times of the day, using the closed-chest left anterior descending coronary artery occlusion model. Following 1 day of reperfusion, hearts subjected to ischemia at the sleep-to-wake transition (zeitgeber time [ZT]12) resulted in 3.5-fold increases in infarct size compared to hearts subjected to ischemia at the wake-to-sleep transition (ZT0). Following 1 month of reperfusion, prior ischemic event at ZT12 versus ZT0 resulted in significantly greater infarct volume, fibrosis, and adverse remodeling, as well as greater depression of contractile function. Genetic ablation of the cardiomyocyte circadian clock (termed cardiomyocyte-specific circadian clock mutant [CCM] mice) attenuated/abolished time-of-day variations in I/R outcomes observed in wild-type hearts. Investigation of Akt and glycogen synthase kinase-3beta in wild-type and CCM hearts identified these kinases as potential mechanistic ties between the cardiomyocyte circadian clock and I/R tolerance.
  
  
  CONCLUSIONS
  We expose a profound time-of-day dependence for I/R tolerance, which is mediated by the cardiomyocyte circadian clock. Further understanding of I/R tolerance rhythms will potentially provide novel insight regarding the etiology and treatment of ischemia-induced cardiac dysfunction.
authors.affiliation: Division of Cardiovascular Diseases, Department of Medicine, University of Alabama at Birmingham, 703 19th St S, ZRB 308, Birmingham, AL 35294, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Durgan
authors.forename: Thomas
authors.initials: T
authors.lastname: Pulinilkunnil
authors.forename: Carolina
authors.initials: C
authors.lastname: Villegas-Montoya
authors.forename: Merissa E
authors.initials: ME
authors.lastname: Garvey
authors.forename: Nikolaos G
authors.initials: NG
authors.lastname: Frangogiannis
authors.forename: Lloyd H
authors.initials: LH
authors.lastname: Michael
authors.forename: Chi-Wing
authors.initials: CW
authors.lastname: Chow
authors.forename: Jason R B
authors.initials: JR
authors.lastname: Dyck
authors.forename: Martin E
authors.initials: ME
authors.lastname: Young
mesh_terms: D056930:ARNTL Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009203:Myocardial Infarction / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000502:physiology*; D010766:Phosphorylation; D010768:Phosphoserine / Q000032:analysis; D011499:Protein Processing, Post-Translational; D020127:Recovery of Function; D012890:Sleep / Q000502:physiology; D013997:Time Factors; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014851:Wakefulness / Q000502:physiology
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; C498260:Dbp protein, mouse; C497441:Nfil3 protein, mouse; D014157:Transcription Factors; D010768:Phosphoserine; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3