Long-term impact of postnatal nutritional programming on cardiac sensitivity to ischemia-reperfusion injury in vivo and on cardio-protective pathways in mice

Abstract

Nutritional disturbances during the postnatal period may be responsible for a predisposition, or “programming”, to increased cardio-metabolic risk and to a progressive alteration of left ventricular contractility in adulthood. Our aim was to evaluate in mice the impact of postnatal overfeeding (PNOF) on cardiac sensitivity to ischemia-reperfusion (I-R) injury in vivo and on the myocardial expression of genes involved in heart protection against ischemia. PNOF was induced by the reduction of litter size of C57/BL6 mice immediately after birth: normally-fed group (NF) was composed of 9 male pups/mother and overfed group (OF) of 3 pups/mother. In vivo I-R injury was induced by the ligation of the anterior interventricular artery for 45 minutes followed by 24h of reperfusion in hearts from 6-months aged mice. The gene expressions of proteins of interest composing the cardioprotective pathways (RISK pathway: Akt, ERK; SAFE pathway: JAK/STAT3; Sirtuins: SIRT1) were measured by RT-qPCR in mice aged 4 and 6 months. PNOF induced in OF group an early and permanent increase in body weight (+ 23%, P < 0.01, N = 11) and a significant increase of infarct size (+ 32%, P < 0.05, N = 11) at 6 months. Hearts OF mice aged 4 months showed a decreased expression of cardioprotective pathways, represented by a reduction in the gene expression of ERK1, Akt, PI3K, STAT3 and SIRT1. At 6 months, the expression of cardioprotective pathways was also reduced in OF group, with the diminution of the gene expression of STAT3, Akt and Erk1. Nutritional programming through short-term PNOF induced a long-lasting decrease in the expression of signaling pathways involved in cardiac cellular protection, which could explain why 6-months old mice show increased susceptibility to myocardial I-R injury in vivo. The mechanism of these alterations needs further exploration, but could involve alterations in cardiomyocyte's balance between apoptotic and regenerative pathways.