title: Sustained hemodynamic stress disrupts normal circadian rhythms in calcineurin-dependent signaling and protein phosphorylation in the heart.
abstract: BACKGROUND
  Despite overwhelming evidence of the importance of circadian rhythms in cardiovascular health and disease, little is known regarding the circadian regulation of intracellular signaling pathways controlling cardiac function and remodeling.
  
  
  OBJECTIVE
  To assess circadian changes in processes dependent on the protein phosphatase calcineurin, relative to changes in phosphorylation of cardiac proteins, in normal, hypertrophic, and failing hearts.
  
  
  RESULTS
  We found evidence of large circadian oscillations in calcineurin-dependent activities in the left ventricle of healthy C57BL/6 mice. Calcineurin-dependent transcript levels and nuclear occupancy of the NFAT (nuclear factor of activated T cells) regularly fluctuated as much as 20-fold over the course of a day, peaking in the morning when mice enter a period of rest. Phosphorylation of the protein phosphatase 1 inhibitor 1 (I-1), a direct calcineurin substrate, and phospholamban, an indirect target, oscillated directly out of phase with calcineurin-dependent signaling. Using a surgical model of cardiac pressure overload, we found that although calcineurin-dependent activities were markedly elevated, the circadian pattern of activation was maintained, whereas, oscillations in phospholamban and I-1 phosphorylation were lost. Changes in the expression of fetal gene markers of heart failure did not mirror the rhythm in calcineurin/NFAT activation, suggesting that these may not be direct transcriptional target genes. Cardiac function in mice subjected to pressure overload was significantly lower in the morning than in the evening when assessed by echocardiography.
  
  
  CONCLUSIONS
  Normal, opposing circadian oscillations in calcineurin-dependent activities and phosphorylation of proteins that regulate contractility are disrupted in heart failure.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8573, USA.
authors.forename: Nita
authors.initials: N
authors.lastname: Sachan
authors.forename: Asim
authors.initials: A
authors.lastname: Dey
authors.forename: David
authors.initials: D
authors.lastname: Rotter
authors.forename: D Bennett
authors.initials: DB
authors.lastname: Grinsfelder
authors.forename: Pavan K
authors.initials: PK
authors.lastname: Battiprolu
authors.forename: Devanjan
authors.initials: D
authors.lastname: Sikder
authors.forename: Victoria
authors.initials: V
authors.lastname: Copeland
authors.forename: Misook
authors.initials: M
authors.lastname: Oh
authors.forename: Erik
authors.initials: E
authors.lastname: Bush
authors.forename: John M
authors.initials: JM
authors.lastname: Shelton
authors.forename: James A
authors.initials: JA
authors.lastname: Bibb
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hill
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Rothermel
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002940:Circadian Rhythm / Q000502:physiology*; D004195:Disease Models, Animal; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology; D006352:Heart Ventricles / Q000378:metabolism; D006439:Hemodynamics / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D054645:Protein Phosphatase 1 / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013312:Stress, Physiological / Q000502:physiology*; D000099211:Phospholamban
chemical_list: D019703:Calcineurin; D002135:Calcium-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D050778:NFATC Transcription Factors; D054645:Protein Phosphatase 1; D011506:Proteins; D000099211:Phospholamban; C511512:DSCR1 protein, mouse