title: FKBP12.6-mediated stabilization of calcium-release channel (ryanodine receptor) as a novel therapeutic strategy against heart failure.
abstract: BACKGROUND
  The development of heart failure is tightly correlated with a decrease in the stoichiometric ratio for FKBP12.6 binding to the ryanodine receptor (RyR) in the sarcoplasmic reticulum (SR). We report that a new drug, the 1,4-benzothiazepine derivative JTV519, reverses this pathogenic process. JTV519 is known to have a protective effect against Ca2+ overload-induced myocardial injury.
  
  
  RESULTS
  Heart failure was produced by 4 weeks of rapid right ventricular pacing, with or without JTV519; SR were then isolated from dog left ventricular (LV) muscles. First, in JTV519-treated dogs, no signs of heart failure were observed after 4 weeks of chronic right ventricular pacing, LV systolic and diastolic functions were largely preserved, and LV remodeling was prevented. Second, JTV519 acutely inhibited both the FK506-induced Ca2+ leak from RyR in normal SR and the spontaneous Ca2+ leak in failing SR. Third, there was no abnormal Ca2+ leak in SR vesicles isolated from JTV519-treated hearts. Fourth, in JTV519-treated hearts, both the stoichiometry of FKBP12.6 binding to RyR and the amount of RyR-bound FKBP12.6 were restored toward the values seen in normal SR. Fifth, in JTV519-untreated hearts, RyR was PKA-hyperphosphorylated, whereas it was reversed in JTV519-treated hearts, returning the channel phosphorylation toward the levels seen in normal hearts.
  
  
  CONCLUSIONS
  During the development of experimental heart failure, JTV519 prevented the amount of RyR-bound FKBP12.6 from decreasing. This in turn reduced the abnormal Ca2+ leak through the RyR, prevented LV remodeling, and led to less severe heart failure.
authors.affiliation: Department of Medical Bioregulation, Division of Cardiovascular Medicine, Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan. yanoma@po.cc.yamaguchi-u.ac.jp
authors.forename: Masafumi
authors.initials: M
authors.lastname: Yano
authors.forename: Shigeki
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Masateru
authors.initials: M
authors.lastname: Kohno
authors.forename: Masahiro
authors.initials: M
authors.lastname: Doi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Tokuhisa
authors.forename: Shinichi
authors.initials: S
authors.lastname: Okuda
authors.forename: Masae
authors.initials: M
authors.lastname: Suetsugu
authors.forename: Takayuki
authors.initials: T
authors.lastname: Hisaoka
authors.forename: Masakazu
authors.initials: M
authors.lastname: Obayashi
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ohkusa
authors.forename: Michihiro
authors.initials: M
authors.lastname: Kohno
authors.forename: Masunori
authors.initials: M
authors.lastname: Matsuzaki
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000494:pharmacology; D004285:Dogs; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D006439:Hemodynamics; D017136:Ion Transport; D008955:Models, Cardiovascular; D009206:Myocardium / Q000378:metabolism; D010766:Phosphorylation; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D016559:Tacrolimus / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000032:analysis / Q000378:metabolism*; D013841:Thiazepines / Q000627:therapeutic use*; D020257:Ventricular Remodeling
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D013841:Thiazepines; C109183:K201 compound; D017868:Cyclic AMP-Dependent Protein Kinases; D022021:Tacrolimus Binding Proteins; C403484:tacrolimus binding protein 1B; D002118:Calcium; D016559:Tacrolimus