Author:

Keywords:

Ventricular arrhythmias, Adrenergic agonists, Heart failure, Myocardial function, Science & Technology, Life Sciences & Biomedicine, Cardiac & Cardiovascular Systems, Cardiovascular System & Cardiology, FK506 BINDING-PROTEIN, RYANODINE RECEPTOR, SARCOPLASMIC-RETICULUM, CA2+ LEAK, HYPERTROPHY, FAILURE, MICE, CONTRACTILITY, ARRHYTHMIAS, MYOCYTES, Animals, Electrocardiography, Heart Failure, Immunoblotting, Male, Mice, Mice, Transgenic, Myocardium, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Tachycardia, Ventricular, Tacrolimus Binding Proteins, Up-Regulation, Ventricular Remodeling, 1102 Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, 3201 Cardiovascular medicine and haematology

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.