CENTRO DE INVESTIGACIONES CARDIOVASCULARES "DR. HORACIO EUGENIO CINGOLANI"
Unidad Ejecutora - UE
congresos y reuniones científicas
Na+/H+ exchanger (NHE-1) hyperactivity is not critically involved in physiological cardiac hypertrophy: role of AKT.
YEVES AM; VILLA-ABRILLE MC; NOLLY MB; PÉREZ NG; ESCUDERO EM; ENNIS IL
San Diego, CA
Congreso; ISHR XXI World Congress; 2013
International Society for Heart Research
NHE-1 hyperactivity plays a key role in pathological cardiac hypertrophy (CH) by increasing intracellular Na+ and Ca2+ concentrations and favouring the activation of calcineurin. Moreover, NHE-1 specific inhibition prevents and/or regresses pathological CH. However, it has not been yet elucidated its putative involvement in physiological CH. Since myocardial stretch, the activator of NHE-1, is a common event in both types of hypertrophy, we speculate that NHE-1 hyperactivity should be involved in both. Physiological CH was induced in rats by swimming (90 min/day, 12 weeks) [biventricular weight/tibia length: 22.0±0.3 vs. 24.3±0.7 mg/mm; sedentary (S) and trained (T); p<0.05]. The hypertrophied myocardium exhibited lower stiffness that correlated with decreased collagen deposition [1.7±0.05 (S) vs. 1.4±0.09 (N); p<0.05]. Up-regulation of PI3-K/P-AKT and P-ERK1/2 was detected in the hypertrophied hearts [PI3-K expression: 153±18 (T) vs. 100±10 (S); P-AKT: 134±10 (T) vs. 100±5 (S); P-ERK1/2: 100± 18% (S) vs 164±17 (T)%]. On the contrary, no significant changes were detected neither in NHE1 [100±8.5 (S) vs. 95±6.7 % (N)] nor in calcineurin [100±10 (S) vs. 96 ±12 (T)] expressions. In isolated rat cardiomyocytes IGF-1 increased cell surface area (111±2 vs. 100±2 %) and protein/DNA ratio (109±1.8 vs. 100±1.5 %). Interestingly, none of these effects were abolished by NHE-1 inhibition. IGF-1 also up-regulated P-AKT (122±5.7 vs. 100±5.9; p<0.05). Furthermore, IGF-I significantly decreased NHE1 activity during pHi recovery induced by sustained acidosis (JH+ at pHi 6.8 mmol/L/min: 1.35±0.28 in IGF-1 vs. 3.02±0.65 in control, p<0.05). Myocardial slow force response, the mechanical counterpart of stretch-induced NHE-1 activation, was significantly reduced in the presence of IGF-I. In conclusion, these results support that NHE1 hyperactivity is not involved in physiological CH development, and seems reasonably to speculate that P-AKT, prevents stretch-induced NHE-1 activation by an inhibitory phosphorylation of the exchanger