title: Conditional FKBP12.6 overexpression in mouse cardiac myocytes prevents triggered ventricular tachycardia through specific alterations in excitation-contraction coupling.
abstract: BACKGROUND
  Ca(2+) release from the sarcoplasmic reticulum via the ryanodine receptor (RyR2) activates cardiac myocyte contraction. An important regulator of RyR2 function is FKBP12.6, which stabilizes RyR2 in the closed state during diastole. Beta-adrenergic stimulation has been suggested to dissociate FKBP12.6 from RyR2, leading to diastolic sarcoplasmic reticulum Ca(2+) leakage and ventricular tachycardia (VT). We tested the hypothesis that FKBP12.6 overexpression in cardiac myocytes can reduce susceptibility to VT in stress conditions.
  
  
  RESULTS
  We developed a mouse model with conditional cardiac-specific overexpression of FKBP12.6. Transgenic mouse hearts showed a marked increase in FKBP12.6 binding to RyR2 compared with controls both at baseline and on isoproterenol stimulation (0.2 mg/kg i.p.). After pretreatment with isoproterenol, burst pacing induced VT in 10 of 23 control mice but in only 1 of 14 transgenic mice (P<0.05). In isolated transgenic myocytes, Ca(2+) spark frequency was reduced by 50% (P<0.01), a reduction that persisted under isoproterenol stimulation, whereas the sarcoplasmic reticulum Ca(2+) load remained unchanged. In parallel, peak I(Ca,L) density decreased by 15% (P<0.01), and the Ca(2+) transient peak amplitude decreased by 30% (P<0.001). A 33.5% prolongation of the caffeine-evoked Ca(2+) transient decay was associated with an 18% reduction in the Na(+)-Ca(2+) exchanger protein level (P<0.05).
  
  
  CONCLUSIONS
  Increased FKBP12.6 binding to RyR2 prevents triggered VT in normal hearts in stress conditions, probably by reducing diastolic sarcoplasmic reticulum Ca(2+) leak. This indicates that the FKBP12.6-RyR2 complex is an important candidate target for pharmacological prevention of VT.
authors: Inserm, U698, Paris, France.
authors: Barnabas
authors: B
authors: Gellen
authors: María
authors: M
authors: Fernández-Velasco
authors: François
authors: F
authors: Briec
authors: Laurent
authors: L
authors: Vinet
authors: Khai
authors: K
authors: LeQuang
authors: Patricia
authors: P
authors: Rouet-Benzineb
authors: Jean-Pierre
authors: JP
authors: Bénitah
authors: Mylène
authors: M
authors: Pezet
authors: Gael
authors: G
authors: Palais
authors: Noémie
authors: N
authors: Pellegrin
authors: Andy
authors: A
authors: Zhang
authors: Romain
authors: R
authors: Perrier
authors: Brigitte
authors: B
authors: Escoubet
authors: Xavier
authors: X
authors: Marniquet
authors: Sylvain
authors: S
authors: Richard
authors: Fréderic
authors: F
authors: Jaisser
authors: Ana María
authors: AM
authors: Gómez
authors: Flavien
authors: F
authors: Charpentier
authors: Jean-Jacques
authors: JJ
authors: Mercadier
mesh_terms: D000200:Action Potentials; D000318:Adrenergic beta-Agonists / Q000633:toxicity; D000818:Animals; D020013:Calcium Signaling; D002304:Cardiac Pacing, Artificial; D002395:Catecholamines / Q000502:physiology; D004318:Doxycycline / Q000494:pharmacology; D007545:Isoproterenol / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010766:Phosphorylation; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000502:physiology; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry / Q000502:physiology*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D017180:Tachycardia, Ventricular / Q000517:prevention & control*; D022021:Tacrolimus Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000318:Adrenergic beta-Agonists; D002395:Catecholamines; D004318:Doxycycline; D007545:Isoproterenol; D011993:Recombinant Fusion Proteins; D019837:Ryanodine Receptor Calcium Release Channel; D022021:Tacrolimus Binding Proteins; C509259:FKBP1B protein, mouse