FKBP12.6 Overexpression Blunts Cardiomyocyte Remodeling After Left-ventricular Pressure-overload

Abstract

Background. Increased open probability of the ryanodine receptor (RyR) has been implicated in the pathophysiology of heart failure. Since association of FK506 binding protein (FKBP12.6) with RyR enhances its closed state we investigated whether FKBP12.6 overexpression could improve cellular remodeling and Ca2+ handling in the setting of pressure-overload. Methods. We used a mouse model with heart-specific and conditional overexpression of FKBP12.6. Wild-type (WT) mice and mice overexpressing FKBP12.6 (TG) were submitted to 10 weeks transverse aortic constriction (TAC) and compared to sham operated animals of the same genotype (SH). Contraction of enzymatically isolated left ventricular myocytes was measured during electrical field stimulation; membrane currents and [Ca2+]i were measured under whole-cell patch clamp, with Fluo-3 as Ca2+ indicator, all at 35°C. Data are shown as mean±SEM. Results. In WT, TAC induced an increase in cell width (from 28±0.7μm in SH to 30±0.9μm in TAC, P<0.05), but not in cell length. This increase was prevented in TG mice (28±0.7μμ ιν ΣH vσ. 28±0.8μμ ιν TAX). At 1 Hz, unloaded cell shortening amplitude was not altered with TAC in both genotypes. However, the prolongation with TAC of time to peak (to 63±3ms vs. 49±2ms, P<0.05) and half-time relaxation (to 98±8ms vs. 77±3ms, P<0.05) in WT was less in TG (to 58±4ms vs. 55±4ms for time to peak and 91±6ms vs. 84±6ms for half-time relaxation). [Ca2+]i transient amplitude, L-type Ca2+ current density and SR Ca2+ content were unchanged with TAC in both genotypes. RyR spontaneous activity (sparks) increased with frequency in SH animals. This frequency effect was reduced by TAC in WT but not in TG animals (P<0.05). Conclusion. FKBP12.6 overexpression reduces cellular hypertrophy and blunts functional remodeling in the setting of pressure-overload.