P4613Long-term impact of postnatal nutritional programming on cardiac sensitivity to ischemia-reperfusion injury in vivo and on cardio-protective pathways in mice

Abstract

Abstract Introduction 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. This nutritional perinatal programming may also lead to an alteration of cellular pathways involved in cardiac protection, such as the specific RISK and SAFE pathways, highlighted during pre- and post-ischemic conditioning or those of sirtuins (SIRT), histone deacetylases involved in the regulation of essential biological process. Purpose 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. Methods 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 ischemia-reperfusion injury was induced by the ligation of the anterior interventricular artery for 45 minutes followed by 24 h 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. Results 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. Conclusion 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, and epigenetic modifications. Acknowledgement/Funding French Fundation