title: Calcineurin inhibitor attenuates the development and induces the regression of cardiac hypertrophy in rats with salt-sensitive hypertension.
abstract: BACKGROUND
  It remains unclear how hemodynamic overload induces cardiac hypertrophy. Recently, activation of calcium-dependent phosphatase, calcineurin, has been elucidated to induce cardiac hypertrophy. In the present study, we examined the role of calcineurin in load-induced cardiac hypertrophy by using Dahl salt-sensitive (DS) rats, which develop both pressure and volume overload when fed a high salt diet.
  
  
  RESULTS
  In the DS rat heart, the activity of calcineurin was increased and cardiac hypertrophy was induced by high salt diet. Treatment of DS rats with the calcineurin inhibitor FK506 (0.1 or 0.01 mg/kg twice daily) from the age of 6 weeks to 12 weeks inhibited the activation of calcineurin in the heart in a dose-dependent manner and attenuated the development of load-induced cardiac hypertrophy and fibrosis without change of hemodynamic parameters. Additionally, treatment with 0.1 mg/kg twice daily but not with 0.01 mg/kg twice daily of FK506 from the age of 12 weeks to 16 weeks induced regression of cardiac hypertrophy in DS rats. Load-induced reprogramming of gene expression was also suppressed by the FK506 treatment.
  
  
  CONCLUSIONS
  These results suggest that calcineurin is involved in the development of cardiac hypertrophy in rats with salt-sensitive hypertension and that inhibition of calcineurin could induce regression of cardiac hypertrophy.
authors.affiliation: Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Shimoyama
authors.forename: D
authors.initials: D
authors.lastname: Hayashi
authors.forename: Y
authors.initials: Y
authors.lastname: Zou
authors.forename: E
authors.initials: E
authors.lastname: Takimoto
authors.forename: M
authors.initials: M
authors.lastname: Mizukami
authors.forename: K
authors.initials: K
authors.lastname: Monzen
authors.forename: S
authors.initials: S
authors.lastname: Kudoh
authors.forename: Y
authors.initials: Y
authors.lastname: Hiroi
authors.forename: Y
authors.initials: Y
authors.lastname: Yazaki
authors.forename: R
authors.initials: R
authors.lastname: Nagai
authors.forename: I
authors.initials: I
authors.lastname: Komuro
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D006332:Cardiomegaly / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004562:Electrocardiography; D004719:Endomyocardial Fibrosis / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006321:Heart / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000150:complications*; D007273:Injections, Intramuscular; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D051381:Rats; D020303:Rats, Inbred Dahl; D012074:Remission Induction; D017673:Sodium Chloride, Dietary; D016559:Tacrolimus / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D065095:Calcineurin Inhibitors; D017673:Sodium Chloride, Dietary; D019703:Calcineurin; D016559:Tacrolimus