Physiological cardiac hypertrophy: Critical role of AKT in the prevention of NHE-1 hyperactivity

Abstract

BackgroundThe involvement of NHE-1 hyperactivity, critical for pathological cardiac hypertrophy (CH), in physiological CH has not been elucidated yet. Stimulation of NHE-1 increases intracellular Na+ and Ca2+ favouring calcineurin activation. Since myocardial stretch, an activator of NHE-1, is common to both types of CH, we speculate that NHE-1 hyperactivity may also happen in physiological CH. However, calcineurin activation is characteristic only for pathological hypertrophy. We hypothesize that an inhibitory AKT-dependent mechanism prevents NHE-1 hyperactivity in the setup of physiological CH. MethodsPhysiological CH was induced in rats by swimming (90min/day, 12weeks) or in cultured isolated cardiomyocytes with IGF-1 (10nmol/L). ResultsTraining induced eccentric CH development (left ventricular weight/tibial length: 22.0±0.3 vs. 24.3±0.7mg/mm; myocyte cross sectional area: 100±3.2 vs. 117±4.1 %; sedentary (Sed) and swim-trained (Swim) respectively; p<0.05] with decreased myocardial stiffness and collagen deposition [1.7±0.05 % (Sed) vs. 1.4±0.09 % (Swim); p<0.05]. Increased phosphorylation of AKT, ERK1/2, p90RSK and NHE-1 at the consensus site for ERK1/2-p90RSK were detected in the hypertrophied hearts (P-AKT: 134±10 vs. 100±5; P-ERK1/2: 164±17 vs. 100±18; P-p90RSK: 160±18 vs. 100±9; P-NHE-1 134±10 vs. 100±10; % in Swim vs. Sed respectively; p<0.05). No significant changes were detected neither in calcineurin activation [calcineurin Aβ 100±10 (Sed) vs. 96±12 (Swim)], nor NFAT nuclear translocation [100±3.11 (Sed) vs. 95±9.81 % (Swim)] nor NHE-1 expression [100±8.5 (Sed) vs. 95±6.7 % (Swim)]. Interestingly, the inhibitory phosphorylation of the NHE-1 consensus site for AKT was increased in the hypertrophied myocardium (151.6±19.4 (Swim) vs. 100±9.5 % (Sed); p<0.05).In isolated cardiomyocytes 24hours IGF-1 increased cell area (114±1.3 %; p<0.05) and protein/DNA content (115±3.9 %, p<0.05), effects not abolished by NHE-1 inhibition with cariporide (114±3 and 117±4.4 %, respectively). IGF-1 significantly decreased NHE-1 activity during pHi recovery from sustained intracellular acidosis (JH+ at pHi 6.8: 4.08±0.74 and 9.09±1.21mmol/L/min, IGF-1 vs. control; p<0.05), and abolished myocardial slow force response, the mechanical counterpart of stretch-induced NHE-1 activation. ConclusionsNHE-1 hyperactivity seems not to be involved in physiological CH development, contrary to what characterizes pathological CH. We propose that AKT, through an inhibitory phosphorylation of the NHE-1, prevents its stretch-induced activation. This posttranslational modification emerges as an adaptive mechanism that avoids NHE-1 hyperactivity preserving its housekeeping functioning.