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

YEVES AM

Sønderborg

Simposio; ACTA PHYSIOLOGICA INTERNATIONAL SYMPOSIUM H+ and HCO3? in Physiology and Pathophysiology 49TH SANDBJERG MEETING ON MEMBRANE TRANSPORT; 2017

ACTA PHYSIOLOGICA INTERNATIONAL SYMPOSIUM. AARUS UNIVERSITY

Aim: Myocardial Na+/H+ exchanger-1(NHE-1) hyperactivity and oxidativestress are interrelated phenomena playing pivotal roles in pathological cardiachypertrophy development and progression to heart failure. Exercisetraining is effective to convert pathological into physiological hypertrophy inthe spontaneously hypertensive rats (SHR) and IGF-1 ?humoral mediator ofexercise training- inhibits myocardialNHE-1, at least in normotensive rats. On the other hand, exercise training hasbeen proposed to have an antioxidant effect. Therefore, we hypothesize thatIGF-1 by hampering NHE-1 hyperactivity and oxidative stress could beresponsible for the cardioprotective effect of training in the SHR. Methods: NHE-1activity [proton efflux (JH+) mmol/L/min], H2O2production, superoxide dismutase (SOD) activity and contractility were measuredin SHR cardiomyocytes. Results: IGF-1significantly decreased NHE-1 activity (JH+ at pHi6.9: 1.98±0.38, n=8 vs. C 3.76±0.53, n=19, p <0.05); effect prevented byAG1024, an antagonist of IGF-1 receptor (3.86±0.97, n=6);by the PI3K inhibitor wortmannin (4.05±0.77 n=5); and the AKT inhibitor MK2206(4.0±0.56, n=14). Moreover, IGF-1 exerted an antioxidant effect as revealed bya significant reduction in H2O2 production accompanied byan increase in SOD activity. In addition, IGF-1 improved cardiomyocytecontractility as evidenced by an increase in sarcomere shortening and adecrease in the relaxation constant. Conclusions:We propose a putative molecularexplanation for the beneficial effect of endurance training on the pathologicalcardiac hypertrophy of the SHR, in which the inhibition of NHE-1hyperactivity, as well as the positive inotropic and antioxidant effect ofIGF-1, emerge as key players.