Back to Search
Start Over
Cardiac FKBP12.6 overexpression protects against triggered ventricular tachycardia in pressure overloaded mouse hearts.
- Source :
-
Basic research in cardiology [Basic Res Cardiol] 2012 Mar; Vol. 107 (2), pp. 246. Date of Electronic Publication: 2012 Feb 04. - Publication Year :
- 2012
-
Abstract
- 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.
- Subjects :
- Animals
Electrocardiography
Heart Failure genetics
Heart Failure metabolism
Heart Failure physiopathology
Immunoblotting
Male
Mice
Mice, Transgenic
Myocardium pathology
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Tachycardia, Ventricular genetics
Tachycardia, Ventricular physiopathology
Tacrolimus Binding Proteins genetics
Up-Regulation
Myocardium metabolism
Tachycardia, Ventricular metabolism
Tacrolimus Binding Proteins metabolism
Ventricular Remodeling genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1435-1803
- Volume :
- 107
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Basic research in cardiology
- Publication Type :
- Academic Journal
- Accession number :
- 22311731
- Full Text :
- https://doi.org/10.1007/s00395-012-0246-8