Cardiac FKBP12.6 overexpression protects against triggered ventricular tachycardia in pressure overloaded mouse hearts.
Alterations in RyR2 function have been proposed as a major pathophysiological mechanism of arrhythmias and heart failure (HF). Cardiac FKBP12.6 overexpression protects against myocardial infarction-induced HF and catecholamine-promoted ventricular arrhythmias. We tested the hypothesis that FKBP12.6 overexpression protects against maladaptive LVH and triggered ventricular arrhythmias following transverse aorta constriction (TAC) in the mouse. The TAC-associated mortality rate was significantly lower in male transgenic (DT) than in Ctr mice (p < 0.05). TAC-associated maladaptive hypertrophy was blunted in DT mice especially 1 month post-TAC and their SERCA2a/PLB ratio remained unchanged 1 and 2 months post-TAC. Two months after TAC, trains of 30 stimuli (burst pacing) performed following isoproterenol injection (0.2 mg/kg, ip), induced VT in 50% of the TAC-Ctr and in none of the TAC-DT mice (p = 0.022). The increase in myocyte shortening and Ca(2+) spark frequency observed in sham-operated Ctr mice in response to 50 nM isoproterenol was reduced in DT mice, and abolished in TAC-DT mice. NCX1 function was reduced in Sham-DT and TAC-DT compared with Sham-Ctr and TAC-Ctr mice, respectively (p < 0.05 for the 2 comparisons). In mice killed after isoproterenol injection and burst pacing, RyR2 S2814 phosphorylation was decreased by 50% in TAC-DT versus TAC-Ctr mice (p < 0.05), with no change in RyR2 S2808 and PLB S16 and T17 phosphorylation. Cardiac FKBP12.6 overexpression in the mouse blunts pressure overload-induced maladaptive LV remodelling and protects against catecholamine-promoted burst pacing-induced ventricular tachycardia by decreasing cardiac sensitivity to adrenergic stress and RyR2 S2814 phosphorylation, and decreasing NCX1 activity.
Université Paris Diderot, Sorbonne Paris Cité and Inserm UMR_S 698, 46, rue Henri Huchard, 75877, Paris Cedex 18, France. laurenvinet@gmail.com
Laurent
L
Vinet
Mylène
M
Pezet
Virginie
V
Bito
François
F
Briec
Liesbeth
L
Biesmans
Patricia
P
Rouet-Benzineb
Barnabas
B
Gellen
Miresta
M
Prévilon
Stefano
S
Chimenti
Jean-Paul
JP
Vilaine
Flavien
F
Charpentier
Karin R
KR
Sipido
Jean-Jacques
JJ
Mercadier
D000818:Animals; D004562:Electrocardiography; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017180:Tachycardia, Ventricular / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D020257:Ventricular Remodeling / Q000235:genetics*
D022021:Tacrolimus Binding Proteins; C509259:FKBP1B protein, mouse