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Cardioprotective role of IGF‐1 in the hypertrophied myocardium of the spontaneously hypertensive rats: A key effect on NHE‐1 activity
Author(s) -
Yeves A. M.,
Burgos J. I.,
Medina A. J.,
VillaAbrille M. C.,
Ennis I. L.
Publication year - 2018
Publication title -
acta physiologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.591
H-Index - 116
eISSN - 1748-1716
pISSN - 1748-1708
DOI - 10.1111/apha.13092
Subject(s) - key (lock) , medicine , cardiology , endocrinology , chemistry , computer science , computer security
Aim Myocardial Na + /H + exchanger‐1 (NHE‐1) hyperactivity and oxidative stress are interrelated phenomena playing pivotal roles in the development of pathological cardiac hypertrophy and heart failure. Exercise training is effective to convert pathological into physiological hypertrophy in the spontaneously hypertensive rats (SHR), and IGF‐1—key humoral mediator of exercise training—inhibits myocardial NHE‐1, at least in normotensive rats. Therefore, we hypothesize that IGF‐1 by hampering NHE‐1 hyperactivity and oxidative stress should exert a cardioprotective effect in the SHR. Methods NHE‐1 activity [proton efflux ( J H+ ) mmol L −1 min −1 ], expression and phosphorylation; H 2 O 2 production; superoxide dismutase (SOD) activity; contractility and calcium transients were measured in SHR hearts in the presence/absence of IGF‐1. Results IGF‐1 significantly decreased NHE‐1 activity ( J H+at pH i 6.95: 1.39 ± 0.32, n = 9 vs C 3.27 ± 0.3, n = 20, P < .05); effect prevented by AG1024, an antagonist of IGF‐1 receptor (2.7 ± 0.4, n = 7); by the PI3K inhibitor wortmannin (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 by a significant reduction in H 2 O 2 production accompanied by an increase in SOD activity. In addition, IGF‐1 improved cardiomyocyte contractility as evidenced by an 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 of the SHR, in which the inhibition of NHE‐1 hyperactivity, as well as the positive inotropic and antioxidant effects, emerges as key players.