Cardioprotective role of IGF-1 in the hypertrophied myocardium of the spontaneously hypertensive rats: A key effect on NHE-1 activity

YEVES, A. M.; BURGOS, J. I.; MEDINA, A. J.; VILLA-ABRILLE, M. C.; ENNIS, I. L.

ACTA PHYSIOLOGICA

WILEY-BLACKWELL PUBLISHING, INC

Año: 2018 p. 1 - 13

1748-1708

AbstractAim: Myocardial Na+/H+ exchanger-1 (NHE-1) hyperactivity and oxidative stressare interrelated phenomena playing pivotal roles in the development of pathologicalcardiac hypertrophy and heart failure. Exercise training is effective to convertpathological into physiological hypertrophy in the spontaneously hypertensive rats(SHR), and IGF-1?key humoral mediator of exercise training?inhibits myocardialNHE-1, at least in normotensive rats. Therefore, we hypothesize that IGF-1by hampering NHE-1 hyperactivity and oxidative stress should exert a cardioprotectiveeffect in the SHR.Methods: NHE-1 activity [proton efflux (JHþ) mmol L1 min1], expression andphosphorylation; H2O2 production; superoxide dismutase (SOD) activity; contractilityand calcium transients were measured in SHR hearts in the presence/absenceof IGF-1.Results: IGF-1 significantly decreased NHE-1 activity (JHþ at pHi 6.95:1.39 0.32, n = 9 vs C 3.27 0.3, n = 20, P < .05); effect prevented byAG1024, an antagonist of IGF-1 receptor (2.7 0.4, n = 7); by the PI3K inhibitorwortmannin (3.14 0.41, n = 7); and the AKT inhibitor MK2206(3.37 0.43, n = 14). Moreover, IGF-1 exerted an antioxidant effect revealed bya significant reduction in H2O2 production accompanied by an increase in SODactivity. In addition, IGF-1 improved cardiomyocyte contractility as evidenced byan increase in sarcomere shortening and a decrease in the relaxation constant,underlined by an increase in the amplitude and rate of decay of the calcium transients.Conclusion: IGF-1 exerts a cardioprotective role on the hypertrophied hearts ofthe SHR, in which the inhibition of NHE-1 hyperactivity, as well as the positiveinotropic and antioxidant effects, emerges as key players.